Role of Proteasomes in Inflammation.

1. The Ubiquitin–Proteasome System

The ubiquitin–proteasome system (UPS) is the most important intracellular non-lysosomal pathway for protein breakdown in eukaryotic cells [ 1 , 2 , 3 ]. As such, it plays a critical role in preserving protein homeostasis and protecting the cells from harmful protein aggregation which would compromise cell integrity and function [ 4 , 5 ].

The UPS is a highly complex mechanism with well over 1000 different genes involved [ 6 ], about only 50 of which encode proteins serving proteasome function [ 7 ]. The vast majority of the remaining UPS genes encode components involved in the selective modification of intracellular substrates with the ubiquitin molecule for recognition and subsequent degradation by proteasomes [ 8 , 9 ]. The covalent attachment of ubiquitin to target proteins is mediated by a cascade reaction involving three enzymes. In the first step, an E1 ubiquitin-activating enzyme uses energy released by adenosine triphosphate (ATP) hydrolysis to form a covalent bond between a cysteine residue of its active site and the C-terminal glycine of ubiquitin [ 10 , 11 ]. The activated ubiquitin is then transferred onto an E2 ubiquitin-conjugating enzyme, which itself can bind to one of several E3 ubiquitin ligases. In the final step, E3 ubiquitin ligases mediate the transfer of ubiquitin to a lysine residue of target substrates [ 12 ] ( Figure 1 ). Less frequently, ubiquitylation occurs on other acceptors sites including cysteine, threonine and serine residues as well as N-terminal methionine [ 12 , 13 , 14 , 15 ]. Remarkably, ubiquitin itself may be also subjected to ubiquitylation at either one of its seven lysine (K) residues (K6, K11, K27, K29, K33, K48 and K63) or its N-terminal methionine (M1—known as linear polyubiquitylation), thereby triggering the formation of poly-ubiquitin chains [ 16 , 17 ]. Depending on the K-linkage used for ubiquitylation, these poly-ubiquitin chains may decide different possible fates for the attached protein [ 18 ]. Among these ubiquitylation types, K48-linked poly-ubiquitin chains represent canonical signals for proteasome-mediated degradation [ 17 , 19 ], while K63-linked and linear (M1) polyubiquitylation may support non-proteolytic roles such as signaling [ 19 , 20 , 21 ]. Importantly, the process of ubiquitylation is counteracted by deubiquitinating enzymes (DUBs) [ 22 ], whose most prominent families include the ubiquitin-specific proteases (USPs) and the otubain proteases (OTUs) [ 23 ].

As alluded earlier, K48-linked ubiquitination is a prerequisite for the breakdown of intracellular proteins by 26S proteasome complexes, which themselves are made up of a 20S core particle (CP) and a 19S regulatory particle (RP) [ 24 , 25 ]. The 20S CP is a barrel-shaped multicatalytic protease consisting of four heptameric αββα rings. The outer two rings are each composed of seven different α-subunits, while the inner two rings each contain seven different β-subunits [ 26 , 27 ]. The catalytic activity of the 20S CP is driven by the β1, β2 and β5 subunits encoded by the PSMB6 , PSMB7 and PSMB5 genes, respectively [ 28 ]. All three β-subunits carry N-terminal threonine active sites exposed to the inner chamber of the 20 CP and exhibit chymotrypsin-, trypsin and caspase-like activities [ 29 ]. The assembly of the 20S CP is a highly coordinated process guided by the proteasome-assembly chaperones (PAC)1-4 encoded by the PSMG1-4 genes and the proteasome maturation protein (POMP) encoded by POMP [ 7 , 30 , 31 ].

Importantly, 20S CPs are usually capped by regulators at either one or both sides of the barrel-shaped structure. One prime example of such regulators is the 19S RP [ 32 ], a complex of approximately 20 subunits which is essential for the recognition of K48-linked polyubiquitinated proteins via the Rpn10 and Rpn13 subunits [ 33 , 34 ]. The 19S RP also ensures the ATP-dependent unfolding of substrates as well as the removal of the ubiquitin moieties before translocation into the 20S CP [ 35 , 36 , 37 ]. Other regulators include the proteasome activators (PA) 28-αβ, PA28-γ and PA200 [ 27 ]. The ability of the 20S CP to bind distinct regulators at both sides gives rise to multiple proteasome complexes whose respective biological relevance, however, remains to be better understood [ 38 ] ( Figure 1 ). Degradation products produced by the UPS are usually 8–10 amino acid long-peptides [ 39 ]. Only a small fraction of them may enter the endoplasmic reticulum (ER) via transporter associated with antigen processing (TAP) and are presented onto major histocompatibility (MHC) class I molecules [ 40 , 41 ]. In this regard, the UPS is a major contributor to MHC class I antigen presentation. Conversely, the vast majority of proteasomal products are further degraded into amino acids by various peptidases.

1.1. Proteasome Isoforms

Besides the β1, β2 and β5 subunits traditionally referred to as standard subunits, proteasomes may incorporate alternative catalytic β-subunits including the inducible β1i (low molecular weight protein 2—LMP2), β2i (multicatalytic endopeptidase complex subunit 1—MECL1) and β5i (LMP7) to form so-called immunoproteasomes (IPs) [ 42 , 43 , 44 ]. While standard proteasomes (SPs) are found in virtually all tissues, IPs are predominantly expressed in immune cells or other cell types that have been exposed to type I and/or II interferons (IFN) [ 43 , 45 ].

It is believed that IPs are more effective than SPs at degrading substrates under stress conditions [ 46 , 47 , 48 , 49 ], thereby protecting the cells from the accumulation of insoluble ubiquitin-modified protein aggregates [ 4 , 43 , 50 ]. It is also understood that SPs and IPs differ in their cleavage rates [ 51 ], thereby modulating the supply of MHC class I-restricted peptide positively or negatively, depending on antigen primary structure [ 6 ]. Recently, IPs have also been shown to regulate inflammation, as discussed below. Apart from the standard and inducible subunits, 20S CPs may contain the β5t catalytic subunit (encoded by the PSMB11 gene) which is exclusively expressed in thymus [ 52 ]. The assembly of β5t results in the formation of so-called thymus-proteasomes which participate in T-cell positive selection [ 52 , 53 ]. Another proteasome isoform is the spermatoproteasome which carries the α4s (encoded by PSMA8 ) alternative structural subunit, predominantly found in testis and involved in spermatogenesis [ 54 ] ( Figure 1 ).

1.2. Proteasomes and Cellular Pro-Inflammatory-Pathways

Due to its ability to degrade multiple regulatory proteins, the UPS coordinates a myriad of cellular responses. Innate immunity is a prime example of such processes, whereby the UPS regulates key signaling cascades. For instance, activation of the NF-κB and MAPK pathways in response to pattern recognition receptors’ (PRRs) engagement typically requires the generation of poly-ubiquitin chains at multiple levels. This is probably best depicted by the linear ubiquitin chain assembly complex (LUBAC) which contains the two E3 ubiquitin ligases HOIL-1L and HOIP [ 55 ]. By promoting the linear (M1-linked) ubiquitination of the IKK regulatory subunit NF-κB essential modulator (NEMO), LUBAC facilitates the phosphorylation of IκBα by IKK [ 55 ]. This phosphorylation serves as a signal for K48-linked poly-ubiquitylation and proteasomal degradation, thereby allowing the translocation of NF-κB into the nucleus for the transcription of genes encoding proinflammatory cytokines [ 56 ]. Further substrates of LUBAC include the receptor-interacting protein kinase 1 (RIPK1) involved in TNF signaling, which following linear ubiquitylation activates the proinflammatory NF-κB and MAPK pathways. The activation of RIPK1 is counterbalanced by the OTU DUB OTULIN, which is able to trim linear ubiquitin linkages [ 57 ]. In addition, K63-linked ubiquitin chains can result in the downstream activation of proinflammatory pathways, which is counteracted by the deubiquitinase A20 [ 58 ] ( Figure 2 ).

Overall, proinflammatory pathways have been shown to be dependent on both proteasomal activity and ubiquitylation [ 6 ]. Toll-like receptor (TLR) stimuli, for example, rely on active IPs for the full induction of proinflammatory cytokines via the MAPK pathway [ 59 , 60 ]. These studies were mainly performed in myeloid-derived immune cells, but lymphoid cells were affected as well [ 61 ]. Interestingly, IP activity was found to play a critical role in T-cell differentiation with inducible subunits favoring T helper (Th)1 and Th17 differentiation, while SPs promoted a regulatory T cell phenotype [ 60 , 62 , 63 ]. B cells, especially plasma cells (PC), have an increased sensitivity to proteotoxic stress and therefore, are extremely dependent on proper proteasome function for their survival [ 64 , 65 , 66 ]. The accumulation of protein aggregates that cannot be effectively degraded by proteasomes generally induces intracellular stress and activates the unfolded protein response (UPR). This, in turn, leads to compensatory mechanisms including the upregulation of proteasome isoforms to restore protein homeostasis [ 6 , 67 ].

2. Impaired Proteasomal Function—(Mono)genetic Defects in the Ubiquitin Proteasome-System in Autoinflammatory Disorders

2.1. Proteasome-Associated-Autoinflammatory-Syndrome (PRAAS)

A cause-and-effect relationship between proteasome dysfunction and chronic inflammation was first established in 2010, as loss-of-function mutations in the PSMB8 gene were identified in patients suffering from autoinflammatory syndromes [ 68 ]. As disease manifestations included j oint contractures, m uscle atrophy, microcytic anemia and p anniculitis-induced lipodystrophy, these syndromes were initially referred to as JMP syndromes. Shortly afterwards, further mutations in the very same PSMB8 gene were found in patients presenting with similar autoinflammatory symptoms. Many different names have been proposed to describe these disorders, including Nakajo-Nishimura syndrome (NNS) [ 69 ], Japanese autoinflammatory syndrome with lipodystrophy (JASL) [ 70 ] and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome [ 71 ]. As these syndromes share the same genetic etiology, these were subsequently brought together and referred to as pr oteasome- a ssociated- a utoinflammatory-syndromes (PRAAS) [ 72 , 73 ].

Disease starts usually in infancy up to early childhood and is characterized by arthritis, skin eruptions, lipodystrophy and myositis as well as muscle atrophy in all PRAAS forms. Recurring fever is also described in all syndromes but JMP. Further PRAAS hallmarks include basal ganglia calcifications and hepatosplenomegaly [ 68 , 69 , 70 , 73 , 74 , 75 ]. As for the skin lesions, they seem to slightly differ in presentation between syndromes, with CANDLE being associated with annular plaque and violaceous eyelids [ 74 ], while NNS and JASL mostly present with nodular erythema [ 69 , 70 ]. Additionally, lesions in JMP patients are described as erythematous macular/papular and nodules [ 68 ].

Laboratory findings are in line with the observed chronic inflammation, as elevated C-reactive protein levels and erythrocyte sedimentation rate are common in patients [ 72 ]. Unfortunately, beside genetic analysis, rapid diagnostic tests for PRAAS are not available so far. However, two biological traits highly specific to PRAAS may be used to help establish the presence of the disease. These include: (i) a typical type I IFN gene signature in the blood [ 7 , 75 , 76 , 77 ] and (ii) a ubiquitous proteasome loss of function. One way to detect type I IFN responses is to monitor the expression of IFN-stimulated genes (ISG) at the transcript level by qPCR and/or Nanostring technology [ 78 , 79 ] or at the protein level (i.e., SIGLEC1) using flow cytometry [ 80 ]. Impaired proteasomal function can be measured either directly using activity-based-probes showing cleavage capacity [ 68 ] or indirectly by assessing the content of ubiquitin-modified proteins by Western blotting [ 69 ].

Given that the first PRAAS genetic mutations were all identified within the PSMB8 gene encoding the catalytic IP subunit β5i [ 71 ], it was initially assumed that these disorders were primarily caused by IP defects. This notion was, however, rapidly challenged by the fact that PRAAS patients may carry genomic alterations in other proteasome genes such as PSMA3 [ 76 ], PSMB4 [ 76 ], PSMB9 [ 76 ], POMP [ 76 , 81 ], PSMG2 [ 82 ] and PSMB10 [ 83 ]. Surprisingly, a series of proteasome loss-of-function mutations affecting PSMB1 [ 84 ], PSMD12 [ 85 ] or PSMC3 [ 86 ] were not associated with typical PRAAS phenotypes, as they were found in patients suffering from neurodevelopmental delay (NDD). While cognitive impairment is also detectable in PRAAS patients, NDD subjects fail to develop any clinical signs of autoinflammation. The reasons for these discrepancies are unclear and warrant further investigation.

Due to the inherent type I IFN gene signature, PRAAS may be placed into the category of interferonopathies. However, in contrast to other well-defined interferonopathies such as Aicardi–Goutières syndrome (AGS) or STING-associated vasculopathy with onset in infancy (SAVI), the molecular mechanisms leading to type I IFN production in PRAAS remain unclear. One particularly attractive hypothesis for the induction of sterile inflammation in PRAAS subjects is the propagation of ER stress. It is indeed well established that ER associated protein degradation (ERAD) function is compromised by proteasome defects, thereby resulting in the retention of misfolded proteins in the ER [ 87 , 88 ]. Perturbed protein homeostasis in the ER lumen is then sensed by the three ER-resident transmembrane receptors ATF6 (activating transcription factor 6), IRE1 (inositol-requiring enzyme 1) and PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase) which in turn initiate the so-called unfolded protein response (UPR). This results in the activation of downstream transcriptions factors destined to upregulate ERAD component and/or chaperones [ 89 ]. Strikingly, it has been shown that sustained UPR activation may induce inflammation even in a pathogen-free context by various mechanisms [ 67 , 90 ]. For instance, the exposure of microglia to proteasome inhibitors leads to the production of inflammatory cytokines in an IRE1-dependent fashion [ 91 ]. The observation that PRAAS patients express typical ER stress markers [ 81 ], suggests that the UPR might be one the mechanisms underlying inflammation in these patients. Interestingly, the activation of the UPR also results in the transcription of genes encoding inhibitors of the mTORC1 signaling pathway [ 92 , 93 , 94 , 95 ]. A decreased activation of mTORC1 would result in decreased lipid biosynthesis and reduced amounts of cholesterol. The observation that cholesterol deficiency is a danger signal alerting the innate immune system [ 96 ] reinforces the notion that the UPR might play a key role in PRAAS pathogenesis.

Thus far, the therapeutic options for PRAAS are extremely limited. Subjects with PRAAS respond poorly to conventional or biologic disease-modifying antirheumatic drugs [ 76 ]. Recently, major advances have been made by introducing the JAK1/2 inhibitor baricitinib into the treatment protocols [ 97 ]. Baricitinib, which blocks inter alia IFN signaling, has shown promising effects in PRAAS patients, as it could reduce disease manifestation in 8 out of 10 patients and promote clinical/inflammatory remission in 5 out of 10 patients, even though one patient had to drop out because of an uncontrolled BK-virus infection [ 97 ]. Similarly, successful treatment of PRAAS with tofacitinib, a pan-JAK-inhibitor, was demonstrated in a case report [ 98 ].

2.2. Further Genetic Inflammatory Diseases with a Link to the UPS

Dysregulated ubiquitylation has recently been associated with NF-κB-related autoinflammatory diseases, also named relopathies [ 99 ]. Among them, three are currently associated with altered ubiquitylation patterns [ 100 ]. These include mutations within genes encoding LUBAC and the OTU-deubiquitinase OTULIN and A20.

Mutations in RBCK , encoding HOIL-1L [ 101 ], and RNF31 , encoding HOIP [ 102 ], are found in patients suffering from autoinflammation and immunodeficiency. These are traditionally referred to as LUBAC-mutations, as they result in the impaired assembly of the LUBAC complex, thereby preventing the linear (M1) ubiquitylation of critical signal transducing proteins (for TNF-signaling RIPK1, as depicted in Figure 2 ). LUBAC deficiency induces cell-type specific and cytokine-specific down- but also upregulation of the NF-κB-pathway. Clinically, patients with mutations in either one of the LUBAC subunits present with multiorgan autoinflammation, recurring infections and intracellular muscular glycogen inclusions with consecutive (cardio-)myopathy (amylopectionsis) [ 101 , 102 ].

OUTLIN, which counteracts linear LUBAC ubiquitylation, may be subjected to several loss-of-function mutations in patients exhibiting enhanced NF-κB activation [ 57 ]. Consequently, this leads to increased secretion of pro-inflammatory cytokines due to unbalanced LUBAC-activity ( Figure 2 ).The resulting disease is named otulipenia or otulin-related autoinflammatory syndrome (ORAS) [ 103 ], whereby patients suffer from recurring fevers, sterile neutrophilia, lipodystrophy, panniculitis and systemic inflammation with growth retardation [ 100 ].

Another DUB involved in a negative feedback regulation is A20, whose alterations are associated with severe autoinflammation. Heterozygous loss-of-function mutations in the gene TNFAIP3 encoding A20 result in a Behçet-like disease named A20 haploinsufficiency [ 104 , 105 ]. Autoinflammation manifests early and is accompanied by bipolar oral and genital ulcers, inflammation of the eyes, exanthemas, and arthralgia/arthritis (ref). Furthermore, mutations within TNFAIP3 have been found in autoimmune–lymphoproliferative syndrome (ALPS) [ 105 ]. In these diseases, autoinflammation is typically accompanied by immunodeficiency due to the severe dysregulation of the NF-κB-pathway [ 100 ] ( Figure 2 ).

USP18 deficiency was recently described as a novel autoinflammatory disorder [ 106 ]. USP18 serves as a negative feedback for type I IFN-signaling besides its role as a DUB for the ubiquitin-like modifier ISG15 [ 107 ]. Genetic mutations resulting in USP18 loss-of-function of present with a pseudo-TORCH (toxoplasmosis, other [syphilis, varicella, mumps, parvovirus and HIV], rubella, cytomegalovirus, and herpes simplex) fetopathy due to the unmitigated IFN-induced inflammation [ 106 ]. Similarly, impaired trafficking of USP18 to the IFN receptor results in loss of USP18 activity and a phenocopy of USP18 deficiency [ 108 ]. Untreated USP18 deficiency results in neonatal death [ 106 ]. However, immediate treatment with JAK-inhibitors has been successful in a first case [ 109 ].

Most recently, mutations within the major E1 ubiquitin-activating enzyme ubiquitin-like modifier activating enzyme 1 (UBA1) have been associated with adult-onset autoinflammation [ 110 , 111 ]. In the affected patients, somatic mutations in peripheral blood myeloid cells in the X-chromosomal UBA1 gene resulted in the expression of a catalytically impaired UBA1 isoform. Mechanistically the impaired ubiquitin-activating activity resulted in decreased polyubiquitylation and increased unfolded protein response. Thus, only males were found to be affected and somatic nature explains the late onset of inflammation. Clinical phenotypes can vary. Common inflammatory manifestations include relapsing perichondritis, Sweet’s syndrome or vasculitis. Additionally, patients frequently present with hematological abnormalities including myelodysplastic syndrome. Due to the vacuoles found in myeloid precursor cells, the affected E 1 enzyme on the X -chromosome, causing a utoinflammation by a s omatic the disease was named VEXAS [ 110 ].

3. Inflammation and Increased Proteasomal Activity

As the inducible β1i, β2i and β5i catalytic units are typically upregulated in response to inflammatory cytokines (as highlighted in the first chapter), the constitutive expression of IPs is a common hallmark of autoinflammatory diseases [ 112 , 113 ]. In this regard, other UPS-related biomarkers include proteasome-directed autoantibodies which were identified in multiple autoimmune diseases such as poly/dermatomyositis, systemic lupus erythematosus (SLE), Sjögren Syndrome (SjS) and multiple sclerosis (MS) [ 114 , 115 , 116 ]. Interestingly, these antibodies were capable of reducing proteasomal activation by PA28, at least in vitro [ 117 ]. Besides autoantibodies against proteasome subunits, circulating proteasomes were also found in various autoinflammatory diseases including SLE, rheumatoid arthritis (RA) or vasculitis [ 118 ]. Interestingly, the amounts of circulating proteasomes seemed to correlate with cellular damage, thereby making them good clinical markers for disease progression [ 119 ]. These findings led to multiple preclinical studies, investigating proteasomal activity in various autoinflammatory diseases and autoimmune diseases [ 59 , 60 , 120 , 121 , 122 , 123 , 124 , 125 ], as discussed below. Additionally, in autoimmune driven diseases further benefit from proteasome inhibition might be accounted to the specific proapoptotic effect on plasma cells [ 64 , 66 , 126 , 127 ].

3.1. Rheumatoid Arthritis

RA is a common autoimmune disease characterized by inflammation of the synovia and joints leading to cartilage and bone destruction [ 128 ]. It can be accompanied by systemic disorders, thereby potentially leading to high morbidity and increased mortality [ 128 ]. A key driver of RA pathogenesis is NF-κB [ 129 ], whose activation relies on proper proteasome function, as mentioned above. Hence, proteasome inhibition has proven clinically useful to reduce the production of interleukin (IL)-1β and IL-6 in T cells from RA patients [ 130 ]. In addition, blocking proteasome function by small molecule inhibitors has been shown to limit RA synovial cell proliferation by preventing the degradation of p53 [ 131 ]. Preclinical data from two mouse models of collagen antibody-induced arthritis and collagen-induced arthritis have also revealed that IP activity supports disease progression by promoting pro-inflammatory cytokine production and inflammatory joint infiltration [ 120 ].

3.2. Systemic Lupus Erythematosus

SLE is an autoimmune disease in which inflammation may target multiple organs, resulting in a very heterogeneous clinical manifestation with individual disease courses and various life-shortening and life-threatening complications [ 132 ]. Autoantibodies found in SLE target nuclear proteins are frequently produced by long-lived plasma cells (PC) that evade conventional B cell-targeted treatment [ 127 ]. However, due to their particularly high-rate production of secretory proteins, PCs generate large amounts of misfolded proteins in ER lumen that must be transported back to the cytosol by ERAD for subsequent degradation by proteasomes. For that reason, PCs are particularly sensitive to proteasome inhibition (as discussed below). A more direct involvement of proteasomes in SLE pathogenesis has been shown in mouse models in which specific IP inhibition was associated with reduced production of IFN-α [ 133 ], a critical disease marker [ 134 ]. Another hint for an active contribution of proteasomes to SLE comes from the observation that PA28γ is downregulated in lupus nephritis tissue [ 135 ]. Since PA28γ-capped proteasomes accelerate the turnover of phosphorylated STAT3 [ 135 ], it is highly likely that the decreased expression of PA28γ actively contributes to diseases pathogenesis. Interestingly, this notion seems to be specific to SLE, as the serum levels of circulating PA28γ in RA, SjS and other undifferentiated connective tissue diseases (CTDs) are increased and positively correlate with disease activity [ 136 ].

3.3. Sjögren Syndrome

Like RA and SLE, SjS is an autoimmune CTD. In SjS, autoimmunity leads to a chronic inflammation of salivatory and lacrimal glands [ 137 ]. It can manifest primarily or in combination with other autoimmune diseases and is the most frequent autoimmune CTD [ 137 ]. Besides the prevalence of anti-proteasome autoantibodies in SjS [ 138 ], the expression of the IP subunit LMP2 was significantly reduced in SjS salivatory glands [ 113 , 139 ]. The downregulation of LMP2 in SjS seems to occur as a consequence of increased protein turnover, as LMP2 mRNA were simultaneously upregulated. mRNA upregulation was most prominent in B cells and correlated with reduced susceptibility to proteasome inhibition [ 140 ]. However, proteasome inhibition in an animal model of SjS prevented disease development [ 141 ]. In this study, the beneficial effect of proteasome inhibitors was attributed to the prevention of Th17 differentiation and lymphocytic gland-infiltration. Furthermore, a variant of the PSMB11 gene encoding the thymoproteasome specific β5t subunit was associated with the development SjS [ 142 ]. In this work, the introduction of this variant in mice resulted in impaired positive T-cell selection and an altered CD8+ T-cell receptor repertoire.

3.4. Inflammatory Bowel Disease

Besides CTD, it has been suspected that UPS dysfunction might be involved in the pathogenesis of other inflammatory diseases. For instance, it is thought that proteasomes participate in the progression of inflammatory bowel disease (IBD). The two main IBD forms are ulcerative colitis (UC) and Crohn’s disease (CD), both of which presents with relapsing chronic inflammation of the gut and sustained activation of the NF-κB pathway [ 143 ]. Strikingly, the IP subunits β1i and β2i were found to be constitutively expressed in colons of patients with CD [ 144 , 145 ] and to a lesser extent in UC [ 145 ]. It has been proposed that the presence of IP in patients with IBD favors IκBα degradation, thereby promoting the excessive activation of NF-κB activation [ 146 ]. IP subunit expression and activity in CD might be involved in immunopathogenesis. However, a prominent role of IFN-γ (known to induce IP formation) in CD limits conclusions made from these ex vivo studies [ 144 ]. Preclinical studies have been carried out to investigate whether such differential expression of proteasome isoforms was disease-relevant. It could be confirmed that both proteasome pan- and IP-specific inhibitions reduced gut inflammation in mice [ 147 , 148 ]. For the targeted approach, a dual inhibition of at least two IP subunits was necessary [ 149 ].The protective mechanism was attributed to reduced NF-κB-signaling in all these studies.

3.5. Multiple Sclerosis

MS is an inflammatory disease of the central nervous system (CNS) resulting in demyelination and neuronal damage [ 150 ]. It is the most common CNS autoimmune disease whose molecular pathogenesis remains, however, poorly understood. It predominantly affects young adults and has a severe impact on the quality of life of these individuals [ 150 ]. Interestingly, LMP2 and PA28αβ were found to be enriched in immune cells and oligodendrocytes of MS lesions [ 151 ]. Further evidence for an involvement of IPs in MS pathogenesis was made by the identification of a PSMB9 variant associated with a reduced risk of developing MS. It is understood that the beneficial effect of this variant is attributed to altered MHC class I-restricted myelin-derived peptides [ 151 ]. It was also shown that proteasome pan-inhibition could prevent the development of experimental autoimmune encephalitis (EAE, a mouse model of MS) in mice following the injection of antigens and/or antigen-specific CD4+ or CD8+ T cells [ 125 , 152 , 153 ]. Similar effects were observed by specifically inhibiting the two IP subunits LMP2 and LMP7 [ 125 , 149 ].

3.6. Further Inflammatory Diseases with a Link to the UPS

The critical role of the UPS in cytokine signaling, especially the NF-κB- and Th17 differentiation pathways makes it a good disease-causing candidate in many other inflammatory disorders. For example, in psoriasis, a chronic inflammatory skin disease, driven by both innate and adaptive immunity, genome wide association studies have shown a direct cause-and-effect relationship between UPS dysfunction and psoriasis [ 154 , 155 ]. A central role here is assigned to the IL-23/Th-17 axis and TNFα a cytokine upregulated by NF-κB [ 156 ]. Similarly, any UPS dysfunction might trigger auto-immune diseases because of inappropriate supply of MHC class I-restricted peptides. This view is supported by a genome wide association study in Behçet’s disease [ 157 ].

4. The UPS as a Therapeutic Target

Bortezomib is the first proteasome inhibitor with FDA approval. It was initially described as an anti-inflammatory drug [ 158 ]. However, bortezomib and the second-generation proteasome inhibitor carfilzomib have only been clinically approved for treating malignancies such as multiple myeloma and mantle cell lymphoma so far [ 159 , 160 , 161 ]. Clinical data from a small study involving 12 patients with SLE [ 64 ] and a randomized double-blind controlled trial with 14 patients with SLE [ 162 ] have shown a beneficial effect of bortezomib on disease outcome. Similarly, in another study, bortezomib was shown to deplete PCs and reduce autoantibody production [ 127 , 163 ]. As discussed earlier, this effect can be easily explained by the fact that antigen-producing PCs need a high proteasomal capacity to degrade misfolded antibodies, which renders them susceptible to proteasome inhibition [ 127 ]. The perceived benefit of bortezomib is its proapoptotic effect on long-lived PCs. This effect is unfortunately not limited to pathogenic PCs but also depletes protective PCs [ 164 ]. Bortezomib has furthermore successfully been used in different cases of autoimmunity including autoimmune cytopenia, refractory primary SjS and encephalitis [ 165 , 166 , 167 , 168 ]. As all beneficial effects of bortezomib on the SLE disease course cannot be attributed to the reduction in autoantibodies [ 162 ], an additional anti-inflammatory effect is suspected. For instance, ex vitro stimulated T cells from healthy donors showed the reduced expression of inflammatory cytokines under proteasome inhibition by bortezomib [ 169 ]. A substantial part of the anti-inflammatory potential might also be attributed to overall cytotoxic effects on immune cells [ 170 ], which were most prominently observed in monocytes [ 124 , 170 ]. Similar effects on antibody formation has been observed in a small case series of anti-NMDA-receptor encephalitis [ 171 ], and a multicenter randomized controlled double-blinded study is currently recruiting patients [ 172 ] (ClinicalTrials identifier NCT03993262 , https://clinicaltrials.gov/ct2/show/NCT03993262 , accessed on 20 February 2021). However, a therapy with bortezomib is limited by the hematological and neurotoxic side effects [ 173 ]. The assumed effects are summarized in Figure 3 .

Further proteasome inhibitors, particularly those only targeting the IP subunits, are currently under investigation [ 174 ], as they are thought to have fewer toxic side effects [ 175 , 176 ]. IP-specific inhibitors have been established in preclinical research [ 120 , 174 ] and have shown promising potential in multiple inflammatory disease models of various inflammatory and autoimmune disorders including experimental arthritis [ 120 ], sepsis-models [ 59 ], experimental autoimmune myocarditis [ 60 ] experimental autoimmune encephalomyelitis [ 125 ] and experimental colitis [ 121 ] inter alia [ 123 , 177 , 178 , 179 ].

For sufficient anti-inflammatory treatment, a co-inhibition of at least two IP catalytic subunits is necessary [ 149 , 179 ]. For immune cell depletion, including PC depletion, at least a partial added inhibitory effect on SPs is needed, as the catalytically active SP subunits β1, β2 and β5 are upregulated compensatory under highly specific IP inhibition in these cells [ 180 ]. The first human immunoproteasome inhibitor with such inhibitory capacity is KZR-616 [ 174 ]. It is currently in clinical phase 2 studies for treating systemic lupus erythematosus (ClinicalTrials identifier NCT03393013 , https://www.clinicaltrials.gov/ct2/show/NCT03393013 , accessed on 20 February 2021) and polymyositis/dermatomyositis (ClinicalTrials identifier NCT04033926 , https://www.clinicaltrials.gov/ct2/show/NCT04033926 , accessed on 20 February 2021).

Whilst proteasome inhibitors are well established, only limited data are currently available on the therapeutic potential of small molecule proteasome activators [ 181 ]. Examples of the very few substances capable of activating proteasomes include a MAPK inhibitor [ 181 ] and the protein kinase (PKA) activator Rolipram, which acts most likely by phosphorylating proteasomes [ 182 ]. Other substances increase proteasomal activity by the transcription of proteasome genes [ 183 ] or by the inhibition of DUBs [ 184 ] Clearly, further research is needed in this field, as increasing proteasome activity may provide treatment for patients with PRAAS or other diseases [ 181 ].

5. Conclusions

To summarize, the UPS is tightly involved in inflammation and (auto-)inflammatory diseases. It is involved in regulating pro-inflammatory pathways and is in turn upregulated during inflammation. Its exact role in the disease pathogenesis of inflammatory diseases is, however, still under investigation. Then again, impaired proteasomal activity is known to induce sterile inflammation, as observed in PRAAS patients. The exact mechanism is still not fully understood. Unravelling the pathogenesis of such diseases further will aid in better therapeutic approaches for PRAAS patients. For (auto-)inflammatory and auto-immune diseases, multiple mechanisms involved have been found. This resulted in successful initial clinical trials using the immunoproteasome as a therapeutic target. Larger studies with novel proteasome inhibitors with an optimized side-effect spectrum seem promising for larger randomized clinical trials.

Acknowledgments

We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité—Universitätsmedizin Berlin.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author Contributions

Literature research: C.C.G., F.E. and T.K.; writing—original draft preparation: C.C.G., F.E. and T.K.; writing—review and editing: C.C.G., F.E. and T.K.; visualization: C.C.G. All authors have read and agreed to the published version of the manuscript.

Funding

C.C.G. is a fellow in the BIH Charité Clinician Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health. The program was initiated and lead by Professor Duska Dragun to enable resident physicians to pursue a career in academic medicine. Professor Dragun passed away on 28 December of 2020. This publication is dedicated to her memory as a mentor, role model and stellar scientist. T.K. is a fellow of the BIH.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Ciechanover A. Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting Cell Death Differ. 2005 12 1178 1190 10.1038/sj.cdd.4401692 16094394

2. Amm I. Sommer T. Wolf D.H. Protein quality control and elimination of protein waste: The role of the ubiquitin–proteasome system Biochim. Biophys. Acta 2014 1843 182 196 10.1016/j.bbamcr.2013.06.031 23850760

3. Pohl C. Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy Science 2019 366 818 822 10.1126/science.aax3769 31727826

4. Warnatsch A. Bergann T. Krüger E. Oxidation matters: The ubiquitin proteasome system connects innate immune mechanisms with MHC class I antigen presentation Mol. Immunol. 2013 55 106 109 10.1016/j.molimm.2012.10.007 23140834

5. Zheng C. Geetha T. Babu J.R. Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases Neurodegener. Dis. 2014 14 161 175 10.1159/000367694 25413678

6. Çetin G. Klafack S. Studencka-Turski M. Krüger E. Ebstein F. The Ubiquitin–Proteasome System in Immune Cells Biomolecules 2021 11 60 10.3390/biom11010060 33466553 PMC7824874

7. Brehm A. Krüger E. Dysfunction in protein clearance by the proteasome: Impact on autoinflammatory diseases Semin. Immunopathol. 2015 37 323 333 10.1007/s00281-015-0486-4 25963519

8. Haas A.L. Siepmann T.J. Pathways of ubiquitin conjugation FASEB J. 1997 11 1257 1268 10.1096/fasebj.11.14.9409544 9409544

9. Pickart C.M. Eddins M.J. Ubiquitin: Structures, functions, mechanisms Biochim. Biophys. Acta 2004 1695 55 72 10.1016/j.bbamcr.2004.09.019 15571809

10. Pickart C.M. Mechanisms Underlying Ubiquitination Annu. Rev. Biochem. 2001 70 503 533 10.1146/annurev.biochem.70.1.503 11395416

11. Pickart C.M. Back to the Future with Ubiquitin Cell 2004 116 181 190 10.1016/S0092-8674(03)01074-2 14744430

12. Berndsen C. Wolberger C. New insights into ubiquitin E3 ligase mechanism Nat. Struct. Mol. Biol. 2014 21 301 307 10.1038/nsmb.2780 24699078

13. McDowell G.S. Kucerova R. Philpott A. Non-canonical ubiquitylation of the proneural protein Ngn2 occurs in both Xenopus embryos and mammalian cells Biochem. Biophys. Res. Commun. 2010 400 655 660 10.1016/j.bbrc.2010.08.122 20807509

14. Cadwell K. Ubiquitination on Nonlysine Residues by a Viral E3 Ubiquitin Ligase Science 2005 309 127 130 10.1126/science.1110340 15994556

15. Vosper J.M. McDowell G.S. Hindley C.J. Fiore-Heriche C.S. Kucerova R. Horan I. Philpott A. Ubiquitylation on Canonical and Non-canonical Sites Targets the Transcription Factor Neurogenin for Ubiquitin-mediated Proteolysis J. Biol. Chem. 2009 284 15458 15468 10.1074/jbc.M809366200 19336407 PMC2708843

16. Mallette F.A. Richard S. K48-linked ubiquitination and protein degradation regulate 53BP1 recruitment at DNA damage sites Cell Res. 2012 22 1221 1223 10.1038/cr.2012.58 22491476 PMC3411168

17. Pickart C.M. Fushman D. Polyubiquitin chains: Polymeric protein signals Curr. Opin. Chem. Biol. 2004 8 610 616 10.1016/j.cbpa.2004.09.009 15556404

18. Akutsu M. Dikic I. Bremm A. Ubiquitin chain diversity at a glance J. Cell Sci. 2016 129 875 880 10.1242/jcs.183954 26906419

19. Grice G.L. Nathan J.A. The recognition of ubiquitinated proteins by the proteasome Cell. Mol. Life Sci. 2016 73 3497 3506 10.1007/s00018-016-2255-5 27137187 PMC4980412

20. Sun L. Chen Z.J. The novel functions of ubiquitination in signaling Curr. Opin. Cell Biol. 2004 16 119 126 10.1016/j.ceb.2004.02.005 15196553

21. Grumati P. Dikic I. Ubiquitin signaling and autophagy J. Biol. Chem. 2018 293 5404 5413 10.1074/jbc.TM117.000117 29187595 PMC5900779

22. Eletr Z.M. Wilkinson K.D. Regulation of proteolysis by human deubiquitinating enzymes Biochim. Biophys. Acta 2014 1843 114 128 10.1016/j.bbamcr.2013.06.027 23845989 PMC3833951

23. Nijman S.M. Luna-Vargas M.P. Velds A. Brummelkamp T.R. Dirac A.M. Sixma T.K. Bernards R. A Genomic and Functional Inventory of Deubiquitinating Enzymes Cell 2005 123 773 786 10.1016/j.cell.2005.11.007 16325574

24. Dahlmann B. Proteasomes Essays Biochem. 2005 41 31 48 10.1042/EB0410031 16250896

25. Tanaka K. Mizushima T. Saeki Y. The proteasome: Molecular machinery and pathophysiological roles Biol. Chem. 2012 393 217 234 10.1515/hsz-2011-0285 23029643

26. Bard J.A. Goodall E.A. Greene E.R. Jonsson E. Dong K.C. Martin A. Structure and Function of the 26S Proteasome Annu. Rev. Biochem. 2018 87 697 724 10.1146/annurev-biochem-062917-011931 29652515 PMC6422034

27. Budenholzer L. Cheng C.L. Li Y. Hochstrasser M. Proteasome Structure and Assembly J. Mol. Biol. 2017 429 3500 3524 10.1016/j.jmb.2017.05.027 28583440 PMC5675778

28. Orlowski M. Wilk S. Catalytic Activities of the 20 S Proteasome, a Multicatalytic Proteinase Complex Arch. Biochem. Biophys. 2000 383 1 16 10.1006/abbi.2000.2036 11097171

29. Kisselev A.F. Songyang Z. Goldberg A.L. Why Does Threonine, and Not Serine, Function as the Active Site Nucleophile in Proteasomes? J. Biol. Chem. 2000 275 14831 14837 10.1074/jbc.275.20.14831 10809725

30. Rousseau A. Bertolotti A. Regulation of proteasome assembly and activity in health and disease Nat. Rev. Mol. Cell Biol. 2018 19 697 712 10.1038/s41580-018-0040-z 30065390

31. Bedford L. Paine S. Sheppard P.W. Mayer R.J. Roelofs J. Assembly, structure, and function of the 26S proteasome Trends Cell Biol. 2010 20 391 401 10.1016/j.tcb.2010.03.007 20427185 PMC2902798

32. Liu C.-W. Jacobson A.D. Functions of the 19S complex in proteasomal degradation Trends Biochem. Sci. 2013 38 103 110 10.1016/j.tibs.2012.11.009 23290100 PMC3557657

33. Deveraux Q. van Nocker S. Mahaffey D. Vierstra R. Rechsteiner M. Inhibition of Ubiquitin-mediated Proteolysis by the Arabidopsis 26 S Protease Subunit S5a J. Biol. Chem. 1995 270 29660 29663 10.1074/jbc.270.50.29660 8530351

34. Husnjak K. Elsasser S. Zhang N. Chen X. Randles L. Shi Y. Hofmann K. Walters K.J. Finley D. Dikic I. Proteasome subunit Rpn13 is a novel ubiquitin receptor Nat. Cell Biol. 2008 453 481 488 10.1038/nature06926 PMC2839886 18497817

35. Smith D.M. Chang S.-C. Park S. Finley D. Cheng Y. Goldberg A.L. Docking of the Proteasomal ATPases’ Carboxyl Termini in the 20S Proteasome’s α Ring Opens the Gate for Substrate Entry Mol. Cell 2007 27 731 744 10.1016/j.molcel.2007.06.033 17803938 PMC2083707

36. Finley D. Recognition and Processing of Ubiquitin-Protein Conjugates by the Proteasome Annu. Rev. Biochem. 2009 78 477 513 10.1146/annurev.biochem.78.081507.101607 19489727 PMC3431160

37. Shin J.Y. Muniyappan S. Tran N.-N. Park H. Lee S.B. Lee B.-H. Deubiquitination Reactions on the Proteasome for Proteasome Versatility Int. J. Mol. Sci. 2020 21 5312 10.3390/ijms21155312 32726943 PMC7432943

38. Dahlmann B. Mammalian proteasome subtypes: Their diversity in structure and function Arch. Biochem. Biophys. 2016 591 132 140 10.1016/j.abb.2015.12.012 26724758

39. Kloetzel P.-M. The proteasome and MHC class I antigen processing Biochim. Biophys. Acta 2004 1695 225 233 10.1016/j.bbamcr.2004.10.004 15571818

40. Seyffer F. Tampé R. ABC transporters in adaptive immunity Biochim. Biophys. Acta Gen. Subj. 2015 1850 449 460 10.1016/j.bbagen.2014.05.022 24923865

41. Townsend A. Trowsdale J. The transporters associated with antigen presentation Semin. Cell Biol. 1993 4 53 61 10.1006/scel.1993.1007 8453065

42. Tanaka K. Role of proteasomes modified by interferon-γ in antigen processing J. Leukoc. Biol. 1994 56 571 575 10.1002/jlb.56.5.571 7964165

43. Ebstein F. Kloetzel P.-M. Krüger E. Seifert U. Krueger E. Emerging roles of immunoproteasomes beyond MHC class I antigen processing Cell. Mol. Life Sci. 2012 69 2543 2558 10.1007/s00018-012-0938-0 22382925 PMC11114860

44. Strehl B. Seifert U. Kruger E. Heink S. Kuckelkorn U. Kloetzel P.-M. Krueger E. Interferon-gamma, the functional plasticity of the ubiquitin-proteasome system, and MHC class I antigen processing Immunol. Rev. 2005 207 19 30 10.1111/j.0105-2896.2005.00308.x 16181324

45. Aki M. Shimbara N. Takashina M. Akiyama K. Kagawa S. Tamura T. Tanahashi N. Yoshimura T. Tanaka K. Ichihara A. Interferon-Gamma Induces Different Subunit Organizations and Functional Diversity of Proteasomes J. Biochem. 1994 115 257 269 10.1093/oxfordjournals.jbchem.a124327 8206875

46. Seifert U. Bialy L.P. Ebstein F. Bech-Otschir D. Voigt A. Schröter F. Prozorovski T. Lange N. Steffen J. Rieger M. Immunoproteasomes Preserve Protein Homeostasis upon Interferon-Induced Oxidative Stress Cell 2010 142 613 624 10.1016/j.cell.2010.07.036 20723761

47. Yun Y.S. Kim K.H. Tschida B. Sachs Z. Noble-Orcutt K.E. Moriarity B.S. Ai T. Ding R. Williams J. Chen L. mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress Mol. Cell 2016 61 625 639 10.1016/j.molcel.2016.01.013 26876939 PMC4870089

48. Niewerth D. Kaspers G.J. Assaraf Y.G. Van Meerloo J. Kirk C.J. Anderl J. Blank J.L. Van De Ven P.M. Zweegman S. Jansen G. Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines J. Hematol. Oncol. 2014 7 7 10.1186/1756-8722-7-7 24418325 PMC3896789

49. Opitz E. Koch A. Klingel K. Schmidt F. Prokop S. Rahnefeld A. Sauter M. Heppner F.L. Völker U. Kandolf R. Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis PLoS Pathog. 2011 7 e1002233 10.1371/journal.ppat.1002233 21909276 PMC3164653

50. Krüger E. Kloetzel P.-M. Immunoproteasomes at the interface of innate and adaptive immune responses: Two faces of one enzyme Curr. Opin. Immunol. 2012 24 77 83 10.1016/j.coi.2012.01.005 22296715

51. Mishto M. Liepe J. Textoris-Taube K. Keller C. Henklein P. Weberruß M. Dahlmann B. Enenkel C. Voigt A. Kuckelkorn U. Proteasome isoforms exhibit only quantitative differences in cleavage and epitope generation Eur. J. Immunol. 2014 44 3508 3521 10.1002/eji.201444902 25231383

52. Murata S. Sasaki K. Kishimoto T. Niwa S.-I. Hayashi H. Takahama Y. Tanaka K. Regulation of CD8+ T Cell Development by Thymus-Specific Proteasomes Science 2007 316 1349 1353 10.1126/science.1141915 17540904

53. Murata S. Takahama Y. Kasahara M. Tanaka K. The immunoproteasome and thymoproteasome: Functions, evolution and human disease Nat. Immunol. 2018 19 923 931 10.1038/s41590-018-0186-z 30104634

54. Kniepert A. Groettrup M. The unique functions of tissue-specific proteasomes Trends Biochem. Sci. 2014 39 17 24 10.1016/j.tibs.2013.10.004 24286712

55. Iwai K. Fujita H. Sasaki Y. Linear ubiquitin chains: NF-κB signalling, cell death and beyond Nat. Rev. Mol. Cell Biol. 2014 15 503 508 10.1038/nrm3836 25027653

56. Alkalay I. Yaron A. Hatzubai A. Orian A. Ciechanover A. Ben-Neriah Y. Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway Proc. Natl. Acad. Sci. USA 1995 92 10599 10603 10.1073/pnas.92.23.10599 7479848 PMC40659

57. Fiil B.K. Gyrd-Hansen M. OTULIN deficiency causes auto-inflammatory syndrome Cell Res. 2016 26 1176 1177 10.1038/cr.2016.113 27686184 PMC5099863

58. Wertz I.E. O’Rourke K.M. Zhou H. Eby M. Aravind L. Seshagiri S. Wu P. Wiesmann C. Baker R.T. Boone D.L. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling Nat. Cell Biol. 2004 430 694 699 10.1038/nature02794 15258597

59. Althof N. Goetzke C.C. Kespohl M. Voss K. Heuser A. Pinkert S. Kaya Z. Klingel K. Beling A. The immunoproteasome-specific inhibitor ONX 0914 reverses susceptibility to acute viral myocarditis EMBO Mol. Med. 2018 10 200 218 10.15252/emmm.201708089 29295868 PMC5801517

60. Bockstahler M. Fischer A. Goetzke C.C. Neumaier H.L. Sauter M. Kespohl M. Müller A.-M. Meckes C. Salbach C. Schenk M. Heart-Specific Immune Responses in an Animal Model of Autoimmune-Related Myocarditis Mitigated by an Immunoproteasome Inhibitor and Genetic Ablation Circulation 2020 141 1885 1902 10.1161/CIRCULATIONAHA.119.043171 32160764

61. Schmidt C. Berger T. Groettrup M. Basler M. Immunoproteasome Inhibition Impairs T and B Cell Activation by Restraining ERK Signaling and Proteostasis Front. Immunol. 2018 9 2386 10.3389/fimmu.2018.02386 30416500 PMC6212513

62. Kalim K.W. Basler M. Kirk C.J. Groettrup M. Immunoproteasome Subunit LMP7 Deficiency and Inhibition Suppresses Th1 and Th17 but Enhances Regulatory T Cell Differentiation J. Immunol. 2012 189 4182 4193 10.4049/jimmunol.1201183 22984077

63. Goetzke C.C. Althof N. Neumaier H.L. Heuser A. Kaya Z. Kespohl M. Klingel K. Beling A. Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection Basic Res. Cardiol. 2021 116 1 16 10.1007/s00395-021-00848-w 33523326 PMC7851025

64. Alexander T. Sarfert R. Klotsche J. Kühl A. Rubbert-Roth A. Lorenz H.-M. Rech J. Hoyer B.F. Cheng Q. Waka A. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus Ann. Rheum. Dis. 2015 74 1474 1478 10.1136/annrheumdis-2014-206016 25710470 PMC4484251

65. Richardson P.G. Barlogie B. Berenson J. Singhal S. Jagannath S. Irwin D. Rajkumar S.V. Srkalovic G. Alsina M. Alexanian R. A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma N. Engl. J. Med. 2003 348 2609 2617 10.1056/NEJMoa030288 12826635

66. Li J. Koerner J. Basler M. Brunner T. Kirk C.J. Groettrup M. Immunoproteasome inhibition induces plasma cell apoptosis and preserves kidney allografts by activating the unfolded protein response and suppressing plasma cell survival factors Kidney Int. 2019 95 611 623 10.1016/j.kint.2018.10.022 30685098

67. Ebstein F. Harlowe M.C.P. Studencka-Turski M. Krüger E. Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS) Front. Immunol. 2019 10 2756 10.3389/fimmu.2019.02756 31827472 PMC6890838

68. Agarwal A.K. Xing C. DeMartino G.N. Mizrachi D. Hernandez M.D. Sousa A.B. De Villarreal L.M. Dos Santos H.G. Garg A. PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome Am. J. Hum. Genet. 2010 87 866 872 10.1016/j.ajhg.2010.10.031 21129723 PMC2997366

69. Arima K. Kinoshita A. Mishima H. Kanazawa N. Kaneko T. Mizushima T. Ichinose K. Nakamura H. Tsujino A. Kawakami A. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome Proc. Natl. Acad. Sci. USA 2011 108 14914 14919 10.1073/pnas.1106015108 21852578 PMC3169106

70. Kitamura A. Maekawa Y. Uehara H. Izumi K. Kawachi I. Nishizawa M. Toyoshima Y. Takahashi H. Standley D.M. Tanaka K. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans J. Clin. Investig. 2011 121 4150 4160 10.1172/JCI58414 21881205 PMC3195477

71. Liu Y. Ramot Y. Torrelo A. Paller A.S. Si N. Babay S. Kim P.W. Sheikh A. Lee C.-C.R. Chen Y. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity Arthritis Rheum. 2011 64 895 907 10.1002/art.33368 PMC3278554 21953331

72. McDermott A. Jacks J. Kessler M. Emanuel P.D. Gao L. Proteasome-associated autoinflammatory syndromes: Advances in pathogeneses, clinical presentations, diagnosis, and management Int. J. Dermatol. 2014 54 121 129 10.1111/ijd.12695 25521013

73. McDermott A. Jesus A.A. Liu Y. Kim P. Jacks J. Sanchez G.A.M. Chen Y. Kannan A. Schnebelen A. Emanuel P.D. A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations J. Am. Acad. Dermatol. 2013 69 e29 e32 10.1016/j.jaad.2013.01.015 23768303 PMC3690515

74. Torrelo A. Patel S. Colmenero I. Gurbindo D. Lendínez F. Hernández A. López-Robledillo J.C. Dadban A. Requena L. Paller A.S. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome J. Am. Acad. Dermatol. 2010 62 489 495 10.1016/j.jaad.2009.04.046 20159315

75. Feist E. Brehm A. Kallinich T. Krüger E. Klinik und Genetik bei Proteasomen-assoziierten autoinflammatorischen Syndromen (PRAAS) Clinical aspects and genetics of proteasome-associated autoinflammatory syndromes (PRAAS) Z. Rheumatol. 2017 76 328 334 10.1007/s00393-017-0264-x 28124745

76. Brehm A. Liu Y. Sheikh A. Marrero B. Omoyinmi E. Zhou Q. Montealegre G. Biancotto A. Reinhardt A. De Jesus A.A. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production J. Clin. Investig. 2015 125 4196 4211 10.1172/JCI81260 26524591 PMC4639987

77. Goldbach-Mansky R. Immunology in clinic review series; focus on autoinflammatory diseases: Update on monogenic autoinflammatory diseases: The role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1 Clin. Exp. Immunol. 2012 167 391 404 10.1111/j.1365-2249.2011.04533.x 22288582 PMC3374271

78. Rice G.I. Melki I. Frémond M.-L. Briggs T.A. Rodero M.P. Kitabayashi N. Oojageer A. Bader-Meunier B. Belot A. Bodemer C. Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease J. Clin. Immunol. 2017 37 123 132 10.1007/s10875-016-0359-1 27943079 PMC5325846

79. Kim H. De Jesus A.A. Brooks S.R. Liu Y. Huang Y. VanTries R. Sanchez G.A.M. Rotman Y. Gadina M. Goldbach-Mansky R. Development of a Validated Interferon Score Using NanoString Technology J. Interf. Cytokine Res. 2018 38 171 185 10.1089/jir.2017.0127 PMC5963606 29638206

80. Orak B. Ngoumou G. Ebstein F. Zieba B. Goetzke C.C. Knierim E. Kaindl A.M. Panzer A. Theophil M. Berns M. SIGLEC1 (CD169) as a potential diagnostical screening marker for monogenic interferonopathies Pediatr. Allergy Immunol. 2021 32 621 625 10.1111/pai.13400 33099809

81. Poli M.C. Ebstein F. Nicholas S.K. De Guzman M.M. Forbes L.R. Chinn I.K. Mace E.M. Vogel T.P. Carisey A.F. Benavides F. Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome Am. J. Hum. Genet. 2018 102 1126 1142 10.1016/j.ajhg.2018.04.010 29805043 PMC5992134

82. De Jesus A.A. Brehm A. VanTries R. Pillet P. Parentelli A.-S. Sanchez G.A.M. Deng Z. Paut I.K. Goldbach-Mansky R. Krüger E. Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy CANDLE/PRAAS4 J. Allergy Clin. Immunol. 2019 143 1939 1943.e8 10.1016/j.jaci.2018.12.1012 30664889 PMC6565382

83. Sarrabay G. Méchin D. Salhi A. Boursier G. Rittore C. Crow Y. Rice G. Tran T.-A. Cezar R. Duffy D. PSMB10, the last immunoproteasome gene missing for PRAAS J. Allergy Clin. Immunol. 2020 145 1015 1017.e6 10.1016/j.jaci.2019.11.024 31783057

84. Ansar M. Ebstein F. Özkoç H. Paracha S. Iwaszkiewicz J. Gesemann M. Zoete V. Ranza E. Santoni F. Sarwar M.T. Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature Hum. Mol. Genet. 2020 29 1132 1143 10.1093/hmg/ddaa032 32129449

85. Küry S. Besnard T. Ebstein F. Khan T.N. Gambin T. Douglas J. Bacino C.A. Sanders S.J. Lehmann A. Latypova X. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder Am. J. Hum. Genet. 2017 100 352 363 10.1016/j.ajhg.2017.01.003 28132691 PMC5294671

86. Kröll-Hermi A. Ebstein F. Stoetzel C. Geoffroy V. Schaefer E. Scheidecker S. Bär S. Takamiya M. Kawakami K. Zieba B. Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress EMBO Mol. Med. 2020 12 11861 10.15252/emmm.201911861 PMC7338805 32500975

87. Nikesitch N. Tao C. Lai K. Killingsworth M. Bae S. Wang M. Harrison S. Roberts T.L. Ling S.C.W. Predicting the response of multiple myeloma to the proteasome inhibitor Bortezomib by evaluation of the unfolded protein response Blood Cancer J. 2016 6 e432 10.1038/bcj.2016.40 27284736 PMC5141355

88. Obeng E.A. Carlson L.M. Gutman D.M. Harrington W.J. Jr. Lee K.P. Boise L.H. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells Blood 2006 107 4907 4916 10.1182/blood-2005-08-3531 16507771 PMC1895817

89. Hetz C. Zhang K. Kaufman R.J. Mechanisms, regulation and functions of the unfolded protein response Nat. Rev. Mol. Cell Biol. 2020 21 421 438 10.1038/s41580-020-0250-z 32457508 PMC8867924

90. Janssens S. Pulendran B. Lambrecht B.N. Emerging functions of the unfolded protein response in immunity Nat. Immunol. 2014 15 910 919 10.1038/ni.2991 25232821 PMC4388558

91. Studencka-Turski M. Çetin G. Junker H. Ebstein F. Krüger E. Molecular Insight into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain Front. Immunol. 2019 10 2900 10.3389/fimmu.2019.02900 31921161 PMC6932173

92. Mazor K.M. Stipanuk M.H. GCN2- and eIF2α-phosphorylation-independent, but ATF4-dependent, induction of CARE-containing genes in methionine-deficient cells Amino Acids 2016 48 2831 2842 10.1007/s00726-016-2318-9 27613409 PMC5107328

93. Ye J. Palm W. Peng M. King B. Lindsten T. Li M.O. Koumenis C. Thompson C.B. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2 Genes Dev. 2015 29 2331 2336 10.1101/gad.269324.115 26543160 PMC4691887

94. Ohoka N. Yoshii S. Hattori T. Onozaki K. Hayashi H. TRB3, a novel ER stress-inducible gene, is induced via ATF4–CHOP pathway and is involved in cell death EMBO J. 2005 24 1243 1255 10.1038/sj.emboj.7600596 15775988 PMC556400

95. Kimball S.R. Jefferson L.S. Induction of REDD1 gene expression in the liver in response to endoplasmic reticulum stress is mediated through a PERK, eIF2α phosphorylation, ATF4-dependent cascade Biochem. Biophys. Res. Commun. 2012 427 485 489 10.1016/j.bbrc.2012.09.074 23000413 PMC3482272

96. York A.G. Williams K.J. Argus J.P. Zhou Q.D. Brar G. Vergnes L. Gray E.E. Zhen A. Wu N.C. Yamada D.H. Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling Cell 2015 163 1716 1729 10.1016/j.cell.2015.11.045 26686653 PMC4783382

97. Sanchez G.A.M. Reinhardt A. Ramsey S. Wittkowski H. Hashkes P.J. Berkun Y. Schalm S. Murias S. Dare J.A. Brown D. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies J. Clin. Investig. 2018 128 3041 3052 10.1172/JCI98814 29649002 PMC6026004

98. Patel P.N. Hunt R. Pettigrew Z.J. Shirley J.B. Vogel T.P. de Guzman M.M. Successful treatment of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome with tofacitinib Pediatr. Dermatol. 2021 10.1111/pde.14517 33512037

99. Steiner A. Harapas C.R. Masters S.L. Davidson S. An Update on Autoinflammatory Diseases: Relopathies Curr. Rheumatol. Rep. 2018 20 39 10.1007/s11926-018-0749-x 29846841

100. Kallinich T. Hinze C. Wittkowski H. Klassifikation autoinflammatorischer Erkrankungen anhand pathophysiologischer Mechanismen Z. Rheumatol. 2020 79 624 638 10.1007/s00393-020-00794-3 32394046

101. Boisson B. Laplantine E. Prando C. Giliani S. Israelsson E. Xu Z. Abhyankar A. Israël L. Trevejo-Nunez G. Bogunovic D. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency Nat. Immunol. 2012 13 1178 1186 10.1038/ni.2457 23104095 PMC3514453

102. Boisson B. Laplantine E. Dobbs K. Cobat A. Tarantino N. Hazen M. Lidov H.G. Hopkins G.W. Du L. Belkadi A. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia J. Exp. Med. 2015 212 939 951 10.1084/jem.20141130 26008899 PMC4451137

103. Zhou Q. Yu X. Demirkaya E. Deuitch N. Stone D. Tsai W.L. Kuehn H.S. Wang H. Yang D. Park Y.H. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease Proc. Natl. Acad. Sci. USA 2016 113 10127 10132 10.1073/pnas.1612594113 27559085 PMC5018768

104. Zhou Q. Wang H. Schwartz D.M. Stoffels M. Park Y.H. Zhang Y. Yang D. Demirkaya E. Takeuchi M. Tsai W.L. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease Nat. Genet. 2016 48 67 73 10.1038/ng.3459 26642243 PMC4777523

105. Takagi M. Ogata S. Ueno H. Yoshida K. Yeh T. Hoshino A. Piao J. Yamashita M. Nanya M. Okano T. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome J. Allergy Clin. Immunol. 2017 139 1914 1922 10.1016/j.jaci.2016.09.038 27845235

106. Meuwissen M.E. Schot R. Buta S. Oudesluijs G. Tinschert S. Speer S.D. Li Z. Van Unen L. Heijsman D. Goldmann T. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome J. Exp. Med. 2016 213 1163 1174 10.1084/jem.20151529 27325888 PMC4925017

107. Basters A. Knobeloch K.-P. Fritz G. USP18—A multifunctional component in the interferon response Biosci. Rep. 2018 38 10.1042/BSR20180250 PMC6240716 30126853

108. Gruber C. Martin-Fernandez M. Ailal F. Qiu X. Taft J. Altman J. Rosain J. Buta S. Bousfiha A. Casanova J.-L. Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy J. Exp. Med. 2020 217 10.1084/jem.20192319 PMC7201920 32092142

109. Alsohime F. Martin-Fernandez M. Temsah M.-H. Alabdulhafid M. Le Voyer T. Alghamdi M. Qiu X. Alotaibi N. Alkahtani A. Buta S. JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency N. Engl. J. Med. 2020 382 256 265 10.1056/NEJMoa1905633 31940699 PMC7155173

110. Beck D.B. Ferrada M.A. Sikora K.A. Ombrello A.K. Collins J.C. Pei W. Balanda N. Ross D.L. Cardona D.O. Wu Z. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease N. Engl. J. Med. 2020 383 2628 2638 10.1056/NEJMoa2026834 33108101 PMC7847551

111. Poulter J. Collins J.C. Cargo C. de Tute R.M. Evans P. Cardona D.O. Bowen D.T. Cunnington J.R. Baguley E. Quinn M. Novel somatic mutations in UBA1 as a cause of VEXAS syndrome Blood 2021 10.1182/blood.2020010286 33690815 PMC8462400

112. Egerer T. Martínez-Gamboa L. Dankof A. Stuhlmüller B. Dorner T. Krenn V. Egerer K. Rudolph P.E. Burmester G.-R. Feist E. Tissue-specific up-regulation of the proteasome subunit β5i (LMP7) in Sjögren’s syndrome Arthritis Rheum. 2006 54 1501 1508 10.1002/art.21782 16646031

113. Krause S. Kuckelkorn U. Dörner T. Burmester G.-R. Feist E. Kloetzel P.-M. Immunoproteasome subunit LMP2 expression is deregulated in Sjogren’s syndrome but not in other autoimmune disorders Ann. Rheum. Dis. 2006 65 1021 1027 10.1136/ard.2005.045930 16414974 PMC1798250

114. Feist E. Dörner T. Kuckelkorn U. Schmidtke G. Micheel B. Hiepe F. Burmester G.R. Kloetzel P.M. Proteasome alpha-type subunit C9 is a primary target of autoantibodies in sera of patients with myositis and systemic lupus erythematosus J. Exp. Med. 1996 184 1313 1318 10.1084/jem.184.4.1313 8879203 PMC2192827

115. Feist E. Kuckelkorn U. Dörner T. Dönitz H. Scheffler S. Hiepe F. Kloetzel P.M. Burmester G.R. Autoantibodies in primary Sjögren’s syndrome are directed against proteasomal subunits of the alpha and beta type Arthritis Rheum. 1999 42 697 702 10.1002/1529-0131(199904)42:4<697::AID-ANR12>3.0.CO;2-H 10211883

116. Mayo I. Arribas J. Villoslada P. Doforno R.A. Rodríguez-Vilariño S. Montalban X. de Sagarra M.R. Castaño J.G. The proteasome is a major autoantigen in multiple sclerosis Brain 2002 125 2658 2667 10.1093/brain/awf274 12429593

117. Brychcy M. Kuckelkorn U. Hausdorf G. Egerer K. Kloetzel P.-M. Burmester G.-R. Feist E. Anti-20S proteasome autoantibodies inhibit proteasome stimulation by proteasome activator PA28 Arthritis Rheum. 2006 54 2175 2183 10.1002/art.21970 16802355

118. Egerer K. Kuckelkorn U. Rudolph P. Rückert J.C. Dörner T. Burmester G.-R. Kloetzel P.-M. Feist E. Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases J. Rheumatol. 2002 29 2045 2052 12375310

119. Maruyama H. Hirayama K. Yamashita M. Ohgi K. Tsujimoto R. Takayasu M. Shimohata H. Kobayashi M. Serum 20S proteasome levels are associated with disease activity in MPO-ANCA-associated microscopic polyangiitis BMC Rheumatol. 2020 4 1 7 10.1186/s41927-020-00137-4 32864569 PMC7447580

120. Muchamuel T. Basler M. Aujay M.A. Suzuki E. Kalim K.W. Lauer C. Sylvain C. Ring E.R. Shields J. Jiang J. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis Nat. Med. 2009 15 781 787 10.1038/nm.1978 19525961

121. Basler M. Dajee M. Moll C. Groettrup M. Kirk C.J. Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome J. Immunol. 2010 185 634 641 10.4049/jimmunol.0903182 20525886

122. Schmidt N. Gonzalez E. Visekruna A. Kühl A. Loddenkemper C. Mollenkopf H. Kaufmann S.H. Steinhoff U. Joeris T. Targeting the proteasome: Partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis Gut 2010 59 896 906 10.1136/gut.2009.203554 20581238

123. Mundt S. Engelhardt B. Kirk C.J. Groettrup M. Basler M. Inhibition and deficiency of the immunoproteasome subunit LMP7 attenuates LCMV-induced meningitis Eur. J. Immunol. 2015 46 104 113 10.1002/eji.201545578 26464284

124. Basler M. Claus M. Klawitter M. Goebel H. Groettrup M. Immunoproteasome Inhibition Selectively Kills Human CD14+ Monocytes and as a Result Dampens IL-23 Secretion J. Immunol. 2019 203 1776 1785 10.4049/jimmunol.1900182 31484727

125. Basler M. Mundt S. Muchamuel T. Moll C. Jiang J. Groettrup M. Kirk C.J. Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis EMBO Mol. Med. 2014 6 226 238 10.1002/emmm.201303543 24399752 PMC3927957

126. Feist E. Burmester G.-R. Krüger E. The proteasome—Victim or culprit in autoimmunity Clin. Immunol. 2016 172 83 89 10.1016/j.clim.2016.07.018 27475228

127. Neubert K. Meister S. Moser K. Weisel F. Maseda D. Amann K. Wiethe C. Winkler T.H. Kalden J.R. Manz R. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis Nat. Med. 2008 14 748 755 10.1038/nm1763 18542049

128. McInnes I.B. Schett G. The Pathogenesis of Rheumatoid Arthritis N. Engl. J. Med. 2011 365 2205 2219 10.1056/NEJMra1004965 22150039

129. Ilchovska D. Barrow M. An Overview of the NF-kB mechanism of pathophysiology in rheumatoid arthritis, investigation of the NF-kB ligand RANKL and related nutritional interventions Autoimmun. Rev. 2021 20 102741 10.1016/j.autrev.2020.102741 33340772

130. van der Heijden J.W. Oerlemans R. Lems W.F. Scheper R.J. Dijkmans B.A. Jansen G. The proteasome inhibitor bortezomib inhibits the release of NFkappaB-inducible cytokines and induces apoptosis of activated T cells from rheumatoid arthritis patients Clin. Exp. Rheumatol. 2009 27 92 98 19327235

131. Migita K. Tanaka F. Yamasaki S. Shibatomi K. Ida H. Kawakami A. Aoyagi T. Kawabe Y. Eguchi K. Regulation of rheumatoid synoviocyte proliferation by endogenous p53 induction Clin. Exp. Immunol. 2001 126 334 338 10.1046/j.1365-2249.2001.01677.x 11703379 PMC1906196

132. Dörner T. Furie R. Novel paradigms in systemic lupus erythematosus Lancet 2019 393 2344 2358 10.1016/S0140-6736(19)30546-X 31180031

133. Ichikawa H.T. Conley T. Muchamuel T. Jiang J. Lee S. Owen T. Barnard J. Nevarez S. Goldman B.I. Kirk C.J. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells Arthritis Rheum. 2012 64 493 503 10.1002/art.33333 21905015 PMC4584406

134. Rose T. Grützkau A. Hirseland H. Huscher D. Dähnrich C. Dzionek A. Ozimkowski T. Schlumberger W. Enghard P. Radbruch A. IFNα and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus Ann. Rheum. Dis. 2012 72 1639 1645 10.1136/annrheumdis-2012-201586 23117242

135. Yao L. Zhou L. Xuan Y. Zhang P. Wang X. Wang T. Meng T. Xue Y. Ma X. Shah A.S. The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity J. Autoimmun. 2019 103 102282 10.1016/j.jaut.2019.05.010 31171475

136. Gruner M. Moncsek A. Rödiger S. Kühnhardt D. Feist E. Stohwasser R. Increased proteasome activator 28 gamma (PA28γ) levels are unspecific but correlate with disease activity in rheumatoid arthritis BMC Musculoskelet. Disord. 2014 15 1 10 10.1186/1471-2474-15-414 25482151 PMC4295294

137. Witte T. Sjögren-Syndrom Z. Rheumatol. 2019 78 511 517 10.1007/s00393-019-0625-8 30937527

138. Feist E. Dörner T. Kuckelkorn U. Scheffler S. Burmester G.-R. Kloetzel P.-M. Diagnostic importance of anti-proteasome antibodies Int. Arch. Allergy Immunol. 2000 123 92 97 10.1159/000024427 11014975

139. Morawietz L. Martinez-Gamboa L. Scheffler S. Hausdorf G. Dankof A. Kuckelkorn U. Doerner T. Egerer K. Burmester G.-R. Faustman D.L. Expression of Proteasomal Immunosubunit ß1i Is Dysregulated in Inflammatory Infiltrates of Minor Salivary Glands in Sjögren’s Syndrome J. Rheumatol. 2009 36 2694 2703 10.3899/jrheum.081098 19833746

140. Martinez-Gamboa L. Lesemann K. Kuckelkorn U. Scheffler S. Ghannam K. Hahne M. Gaber-Elsner T. Egerer K. Naumann L. Buttgereit F. Gene Expression of Catalytic Proteasome Subunits and Resistance Toward Proteasome Inhibition of B Lymphocytes from Patients with Primary Sjögren Syndrome J. Rheumatol. 2013 40 663 673 10.3899/jrheum.120680 23504381

141. Xiaohui W. Lingyun S. Tian J. Wang X. Chen Q. Rui K. Ma J. Wang S. Wang Q. Wang X. Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome Cell. Mol. Immunol. 2017 14 924 934 10.1038/cmi.2017.8 28690324 PMC5675963

142. Nitta T. Kochi Y. Muro R. Tomofuji Y. Okamura T. Murata S. Suzuki H. Sumida T. Yamamoto K. Takayanagi H. Human thymoproteasome variations influence CD8 T cell selection Sci. Immunol. 2017 2 eaan5165 10.1126/sciimmunol.aan5165 28783658

143. Schreiber S. Nikolaus S. Hampe J. Activation of nuclear factor kappa B in inflammatory bowel disease Gut 1998 42 477 484 10.1136/gut.42.4.477 9616307 PMC1727068

144. Visekruna A. Slavova N. Dullat S. Gröne J. Kroesen A.-J. Ritz J.-P. Buhr H.-J. Steinhoff U. Expression of catalytic proteasome subunits in the gut of patients with Crohn’s disease Int. J. Color. Dis. 2009 24 1133 1139 10.1007/s00384-009-0679-1 19274467 PMC2733182

145. Visekruna A. Joeris T. Schmidt N. Lawrenz M. Ritz J.-P. Buhr H.J. Steinhoff U. Comparative expression analysis and characterization of 20S proteasomes in human intestinal tissues Inflamm. Bowel Dis. 2009 15 526 533 10.1002/ibd.20805 19067411

146. Visekruna A. Joeris T. Seidel D. Kroesen A. Loddenkemper C. Zeitz M. Kaufmann S.H. Schmidt-Ullrich R. Steinhoff U. Proteasome-mediated degradation of IκBα and processing of p105 in Crohn disease and ulcerative colitis J. Clin. Investig. 2006 116 3195 3203 10.1172/JCI28804 17124531 PMC1654202

147. Moallemian R. Rehman A.U. Zhao N. Wang H. Chen H. Lin G. Ma X. Yu J. Immunoproteasome inhibitor DPLG3 attenuates experimental colitis by restraining NF-κB activation Biochem. Pharmacol. 2020 177 113964 10.1016/j.bcp.2020.113964 32278007

148. Vachharajani N. Joeris T. Luu M. Hartmann S. Pautz S. Jenike E. Pantazis G. Prinz I. Hofer M.J. Steinhoff U. Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7 Oncotarget 2017 8 50447 50459 10.18632/oncotarget.14579 28881574 PMC5584149

149. Basler M. Lindstrom M.M. LaStant J.J. Bradshaw J.M. Owens T.D. Schmidt C. Maurits E. Tsu C. Overkleeft H.S. Kirk C.J. Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity EMBO Rep. 2018 19 10.15252/embr.201846512 PMC6280796 30279279

150. Thompson A.J. Baranzini S. Geurts J. Hemmer B. Ciccarelli O. Multiple sclerosis Lancet 2018 391 1622 1636 10.1016/S0140-6736(18)30481-1 29576504

151. Mishto M. Bellavista E. Ligorio C. Textoris-Taube K. Santoro A. Giordano M. D’Alfonso S. Listì F. Nacmias B. Cellini E. Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population PLoS ONE 2010 5 e9287 10.1371/journal.pone.0009287 20174631 PMC2823778

152. VanderLugt C.L. Rahbe S.M. Elliott P.J. Canto M.C.D. Miller S.D. Treatment of Established Relapsing Experimental Autoimmune Encephalomyelitis with the Proteasome Inhibitor PS-5191 J. Autoimmun. 2000 14 205 211 10.1006/jaut.2000.0370 10756082

153. Hosseini H. André P. Lefevre N. Viala L. Walzer T. Peschanski M. Lotteau V. Protection against experimental autoimmune encephalomyelitis by a proteasome modulator J. Neuroimmunol. 2001 118 233 244 10.1016/S0165-5728(01)00352-6 11498258

154. Gupta R. Debbaneh M.G. Liao W. Genetic Epidemiology of Psoriasis Curr. Dermatol. Rep. 2014 3 61 78 10.1007/s13671-013-0066-6 25580373 PMC4285384

155. Yang L. Guo W. Zhang S. Wang G. Ubiquitination-proteasome system: A new player in the pathogenesis of psoriasis and clinical implications J. Dermatol. Sci. 2018 89 219 225 10.1016/j.jdermsci.2017.12.002 29279285

156. Boehncke W.-H. Schön M.P. Psoriasis Lancet 2015 386 983 994 10.1016/S0140-6736(14)61909-7 26025581

157. Bakir-Gungor B. Remmers E.F. Meguro A. Mizuki N. Kastner D.L. Gül A. Sezerman O.U. Identification of possible pathogenic pathways in Behçet’s disease using genome-wide association study data from two different populations Eur. J. Hum. Genet. 2014 23 678 687 10.1038/ejhg.2014.158 25227143 PMC4402634

158. Sánchez-Serrano I. Success in translational research: Lessons from the development of bortezomib Nat. Rev. Drug Discov. 2006 5 107 114 10.1038/nrd1959 16518378

159. Stewart A.K. Rajkumar S.V. Dimopoulos M.A. Masszi T. Špička I. Oriol A. Hájek R. Rosiñol L. Siegel D.S. Mihaylov G.G. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma N. Engl. J. Med. 2015 372 142 152 10.1056/NEJMoa1411321 25482145

160. Richardson P. Sonneveld P. Schuster M. Irwin D. Stadtmauer E. Facon T. Harousseau J.-L. Ben-Yehuda D. Lonial S. Goldschmidt H. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma N. Engl. J. Med. 2005 352 2487 2498 10.1056/NEJMoa043445 15958804

161. Manasanch E.E. Orlowski R.Z. Proteasome inhibitors in cancer therapy Nat. Rev. Clin. Oncol. 2017 14 417 433 10.1038/nrclinonc.2016.206 28117417 PMC5828026

162. Ishii T. Tanaka Y. Kawakami A. Saito K. Ichinose K. Fujii H. Shirota Y. Shirai T. Fujita Y. Watanabe R. Multicenter double-blind randomized controlled trial to evaluate the effectiveness and safety of bortezomib as a treatment for refractory systemic lupus erythematosus Mod. Rheumatol. 2018 28 986 992 10.1080/14397595.2018.1432331 29363990

163. Van Dam L.S. Osmani Z. Kamerling S.W. Kraaij T. Bakker J. Scherer H.U. Rabelink T.J. Voll R. Alexander T. Isenberg D. A reverse translational study on the effect of rituximab, rituximab plus belimumab, or bortezomib on the humoral autoimmune response in SLE Rheumatology 2020 59 2734 2745 10.1093/rheumatology/kez623 31951278 PMC7516125

164. Hiepe F. Radbruch F.H.A. Plasma cells as an innovative target in autoimmune disease with renal manifestations Nat. Rev. Nephrol. 2016 12 232 240 10.1038/nrneph.2016.20 26923204

165. Knops N. Emonds M. Herman J. Levtchenko E. Mekahli D. Pirenne J. Van Geet C. Dierickx D. Bortezomib for autoimmune hemolytic anemia after intestinal transplantation Pediatr. Transplant. 2020 24 13700 10.1111/petr.13700 32166874

166. Beydoun S.B. Persaud Y. Lafferty J. Callaghan M.U. Savaşan S. Bortezomib treatment of steroid-refractory Evans syndrome in children Pediatr. Blood Cancer 2020 67 28725 10.1002/pbc.28725 32969165

167. Yates S. Matevosyan K. Rutherford C. Shen Y.-M. Sarode R. Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: A case report Transfusion 2014 54 2064 2067 10.1111/trf.12614 24655327

168. Jakez-Ocampo J. Atisha-Fregoso Y. Llorente L. Refractory Primary Sjögren Syndrome Successfully Treated with Bortezomib J. Clin. Rheumatol. 2015 21 31 32 10.1097/RHU.0000000000000210 25539431

169. Berges C. Haberstock H. Fuchs D. Miltz M. Sadeghi M. Opelz G. Daniel V. Naujokat C. Proteasome inhibition suppresses essential immune functions of human CD4+T cells Immunology 2008 124 234 246 10.1111/j.1365-2567.2007.02761.x 18217957 PMC2566628

170. Pletinckx K. Vaßen S. Schlusche I. Nordhoff S. Bahrenberg G. Dunkern T.R. Inhibiting the immunoproteasome’s β5i catalytic activity affects human peripheral blood-derived immune cell viability Pharmacol. Res. Perspect. 2019 7 e00482 10.1002/prp2.482 31236277 PMC6581949

171. Scheibe F. Prüss H. Mengel A.M. Kohler S. Nümann A. Köhnlein M. Ruprecht K. Alexander T. Hiepe F. Meisel A. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis Neurology 2016 88 366 370 10.1212/WNL.0000000000003536 28003505

172. Wickel J. Chung H.-Y. Platzer S. Lehmann T. Prüss H. Leypoldt F. Günther A. Scherag A. Geis C. on behalf of the GENERATE Study Group Generate-Boost: Study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis Trials 2020 21 1 12 10.1186/s13063-020-04516-7 32641101 PMC7346383

173. Meregalli C. An Overview of Bortezomib-Induced Neurotoxicity Toxics 2015 3 294 303 10.3390/toxics3030294 29051465 PMC5606681

174. Johnson H.W.B. Lowe E. Anderl J.L. Fan A. Muchamuel T. Bowers S. Moebius D.C. Kirk C. McMINN D.L. Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2S,3R)-N-((S)-3-(Cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propenamide) J. Med. Chem. 2018 61 11127 11143 10.1021/acs.jmedchem.8b01201 30380863

175. Von Brzezinski L. Säring P. Landgraf P. Cammann C. Seifert U. Dieterich D.C. Low neurotoxicity of ONX-0914 supports the idea of specific immunoproteasome inhibition as a side-effect-limiting, therapeutic strategy Eur. J. Microbiol. Immunol. 2017 7 234 245 10.1556/1886.2017.00025 PMC5632751 29034113

176. Thibaudeau T.A. Smith D.M. A Practical Review of Proteasome Pharmacology Pharmacol. Rev. 2019 71 170 197 10.1124/pr.117.015370 30867233 PMC6423620

177. Zilberberg J. Matos J. Dziopa E. Dziopa L. Yang Z. Kirk C.J. Assefnia S. Korngold R. Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen–Disparate Murine Model Biol. Blood Marrow Transplant. 2015 21 1555 1564 10.1016/j.bbmt.2015.06.010 26093043

178. Liu H. Wan C. Ding Y. Han R. He Y. Xiao J. Hao J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T h 17-cell differentiation and regulating cytokine production FASEB J. 2016 31 1756 1766 10.1096/fj.201601147R 28096232

179. Basler M. Groettrup M. Recent insights how combined inhibition of immuno/proteasome subunits enables therapeutic efficacy Genes Immun. 2020 21 273 287 10.1038/s41435-020-00109-1 32839530

180. Ladi E. Everett C. Stivala C.E. Daniels B.E. Durk M.R. Harris S.F. Huestis M.P. Purkey H.E. Staben S.T. Augustin M. Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability J. Med. Chem. 2019 62 7032 7041 10.1021/acs.jmedchem.9b00509 31283222

181. Leestemaker Y. De Jong A. Witting K.F. Penning R. Schuurman K. Rodenko B. Zaal E.A. Van De Kooij B. Laufer S. Heck A.J. Proteasome Activation by Small Molecules Cell Chem. Biol. 2017 24 725 736.e7 10.1016/j.chembiol.2017.05.010 28552582

182. Myeku N. Clelland C.L. Emrani S. Kukushkin N.V. Yu W.H. Goldberg A.L. Duff K. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling Nat. Med. 2016 22 46 53 10.1038/nm.4011 26692334 PMC4787271

183. Liu Y. Hettinger C.L. Zhang D. Rezvani K. Wang X. Wang H. Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington’s disease J. Neurochem. 2014 129 539 547 10.1111/jnc.12647 24383989 PMC3997618

184. Lee B.-H. Lee M.J. Park S. Oh D.-C. Elsasser S. Chen P.-C. Gartner C. Dimova N. Hanna J.V. Gygi S.P. Enhancement of proteasome activity by a small-molecule inhibitor of USP14 Nat. Cell Biol. 2010 467 179 184Bico 10.1038/nature09299 PMC2939003 20829789