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Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease.

Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increas

The role of mesenchymal stem cells in attenuating inflammatory bowel disease through ubiquitination.

Inflammatory bowel disease (IBD), a condition of the digestive tract and one of the autoimmune diseases, is becoming a disease of significant global public health concern and substantial clinical burden. Various signaling pathways have been documented to modulate IBD, but the exact activation and regulatory mechanisms have not been fully clarified; thus, a need for constant exploration of the molecules and pathways that play key roles in the development of IBD. In recent years, several protein post-translational modification pathways, such as ubiquitination, phosphorylation, methylation, acety

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… E2 | E2 dominates the determination of ubiquitination and polyubiquitination and attaches ubiquitin peptides to the substrate. … Inhibition of the E3 ligase TRIM16 effectively increases the formation of K48-linked polyubiquitin chains on NIK ( 122 ). …

Ubiquitylomics: An Emerging Approach for Profiling Protein Ubiquitylation in Skeletal Muscle.

Skeletal muscle is a highly adaptable tissue, finely tuned by various physiological and pathological factors. Whilst the pivotal role of skeletal muscle in overall health is widely acknowledged, unravelling the underlying molecular mechanisms poses ongoing challenges. Protein ubiquitylation, a crucial post-translational modification, is involved in regulating most biological processes. This widespread impact is achieved through a diverse set of enzymes capable of generating structurally and functionally distinct ubiquitin modifications on proteins. The complexity of protein ubiquitylation has

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… The high stoichiometry of K33‐linked polyubiquitin chains was a distinct feature of muscle, as most other mouse tissues were dominated by K48‐linked polyubiquitin chains. Ubiquitin protein standard absolute quantification (Ub‐PSAQ) is another method for absolute quantification of ubiquitin [ 47 ]. … Ohtake F., Saeki Y., Sakamoto K., et al., “Ubiquitin Acetylation Inhibits Polyubiquitin Chain Elongation,” EMBO Reports 16, no. 2 (2015): 192–201. 75. Rebelo‐Marques A., Lages A. D. …

Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome.

Skeletal muscle adapts its mass as consequence of physical activity, metabolism and hormones. Catabolic conditions or inactivity induce signaling pathways that regulate the process of muscle loss. Muscle atrophy in adult tissue occurs when protein degradation rates exceed protein synthesis. Two major protein degradation pathways, the ubiquitin-proteasome and the autophagy-lysosome systems, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These degradation systems are controlled by a transcription dependent program that modulates the expression of rate-lim

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… Lys48-linked polyubiquitin chains are a signal for proteasome-dependent degradation, but Lys63-linked polyubiquitin chains play other roles, such as regulating autophagy-dependent cargo recognition by interacting with the scaffold protein p62 (also known as SQSTM1) ( Kirkin et al., 2009; Komatsu et al … Notably, muscle-specific TRAF6 knockout mice have a decreased amount of polyubiquitinated proteins, almost no Lys63-polyubiquitinated proteins in starved muscles ( Paul et al., 2012 ) and are resistant to muscle loss induced by denervation, cancer or starvation ( Kumar et al., 2012; Paul et al., 2010 …

Regulation of HDAC6 Catalytic Activity in Cancer: The Role of Post-Translational Modifications and Protein-Protein Interactions.

Histone deacetylase 6 (HDAC6) is a large multidomain protein that deacetylates lysine residues on cytoplasmic proteins, influencing numerous cellular processes. Both the catalytic and noncatalytic functions of HDAC6 have been implicated in cancer development and progression. Over a decade of research on catalytic domain inhibitors has shown that these drugs are well tolerated, exhibit anticancer activity, and can alleviate chemotherapy-induced peripheral neuropathies. However, their effectiveness in treating solid tumours remains uncertain. HDAC6 activity is regulated by protein-protein intera

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… While many ubiquitin-binding proteins facilitate proteasomal degradation by recognising lysine 48-linked polyubiquitin chains, HDAC6’s ubiquitin-binding domain binds lysine 63-linked polyubiquitin chains, assisting in the sequestration and transport of aggregated proteins [ 119 ]. … Thus, binding between free ubiquitin and the HDAC6 ZnF-UBP domain would decrease its binding to polyubiquitinated proteins, where the recycling of free ubiquitin regulates the turnover of misfolded proteins [ 118 ]. …

The Role of the Ubiquitin System in Eye Diseases.

The ubiquitin-proteasome system (UPS) is a fundamental process that regulates various biological functions, including immune response, cell cycle, oxidative stress, migration, and cellular proliferation. This system is responsible for the degradation of proteins, while proteasomes play a significant role in mechanisms involved in health and human diseases. The participation of the UPS in immune response is particularly relevant, leading to the involvement of immunoproteasomes. This specialized proteasome is involved in the processing and presentation of antigenic peptides, making it crucial fo

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… polyubiquitination). … Rpn10 is associated with polyubiquitin while Rpn1-Rpn2 binds to the protein. …

Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor-mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation.

Melanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high-resolution mass spectrometry, and other techniques such as

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… Considering the central role of polyubiquitination in protein degradation, we co‐transfected B16 and A375 cells with plasmids expressing ubiquitin (HA‐Ub) and CIP2A (Flag‐CIP2A) in melanoma cells. … Immunoprecipitation using anti‐Flag antibody followed by detection with anti‐HA antibody showed that knockdown of VHL significantly reduced PF‐induced CIP2A polyubiquitination (Figure 6I ), indicating that PF probably induces CIP2A polyubiquitination through VHL. …

USP33 Promotes Lung Adenocarcinoma Brain Metastasis by Inhibiting the K48-Linked Ubiquitination and Degradation of S100A9 and Facilitating Vimentin Secretion.

Brain metastasis has a deterministic influence on the evolutionary trajectory of lung adenocarcinoma (LUAD). Given the profound clinical importance of LUAD brain metastases and the formidable obstacles that hinder their precise prediction, novel therapeutic targets are urgently needed. Notably, a substantial fraction of lung carcinoma cells in brain metastatic foci demonstrates marked S100A9 overexpression. However, whether these cells represent the primary drivers of brain metastasis requires further elucidation. Coculture of S100A9-overexpressing LUAD cells with human brain microvascular end

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… Figure 8 USP33 removes K48-linked polyubiquitin chains on S100A9 to stabilize its expression and promote Vimentin secretion. … USP33 preferentially hydrolyzes K48-linked polyubiquitin chains on S100A9, thereby preventing its proteasomal degradation, which corroborates the established enzymatic specificity of USP33. …

Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance.

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literat

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… In the degradation process, the polyubiquitinated proteins are unfolded and recognized by the 26S proteasome, with ATP hydrolysis to AMP. … The 20S CP generally mediates the cleavage/degradation of polyubiquitinated protein substrates that have been unfolded by the 19S RP into small peptides and amino acids [ 2 , 22 ]. …

Знаменитый ингибатор CEP-18770 Наводит на смерть клеток в Медульлобластоме.

Medulloblasoma (MBs) представляют собой наиболее распространенные злокачественные твердые опухоли у детей. Обычный режим лечения БМ включает хирургическое удаление опухоли, за которым следуют радиация и химиотерапия. Однако этот подход связан со значительной заболеваемостью и пагубными побочными последствиями. Таким образом, существует острая потребность в более точных и менее вредных методах лечения для повышения качества жизни выживших жертв. CEP-18770, новый протеазонный ингибитор, нацеленный на подразделение 20S, стал многообещающим кандидатом, благодаря его антирактерной активности в мета

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… Polyubiquitin was detected by anti-ubiquitin antibody on the total lysate of the cells. +: 1.2 uM MG-132, 0.125 nM Carfilzomib, 7.5 pM CEP-18770. ++: 2.4 uM MG-132, 0.25 nM Carfilzomib, 15 pM CEP-18770. … MG-132, Carfilzomib, and CEP-18770 induced the accumulation of polyubiquitin proteins, resulting in an increased smear of protein in comparison to the control. These results show that novel PIs are very effective in reducing cell viability of MBs. …

Bortezomib treatment causes long-term testicular dysfunction in young male mice.

BackgroundWith increased long-term survivors of childhood cancer patients, therapy-associated infertility has become one of the most common late side-effects and significantly affects their life-quality. Therefore, evaluation of anti-cancer agents on male reproduction and infertility prevention are urgently demanding. The proteasome inhibitor bortezomib has been launched in clinical trials for childhood cancers, however, its potential side effects on reproduction have so far been neither investigated experimentally nor reported in treated children. Thus the present study is designed to explore

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… Indeed, it has been observed that targeted disruption of the polyubiquitin gene Ubb results in male and female infertility [ 16 ] and altered testicular gene expression patterns [ 17 ]. … gene Ubb is essential for meiotic progression Mol Cell Biol 2008 28 1136 1146 18070917 10.1128/MCB.01566-07 PMC2223379 Sinnar SA Small CL Evanoff RM Reinholdt LG Griswold MD Kopito RR Ryu KY Altered testicular gene expression patterns in mice lacking the polyubiquitin gene Ubb Mol Reprod Dev 2011 78 …

The ubiquitin-proteasome system in the tumor immune microenvironment: a key force in combination therapy.

The ubiquitin-proteasome system (UPS) plays a crucial role in modulating the proliferation, activation, and normal functioning of immune cells through the regulation of protein degradation and function. By influencing the expression of immune checkpoint-associated proteins, the UPS modulates T cell-mediated anti-tumor immune responses and can potentially facilitate the immune escape of tumor cells. Additionally, the UPS contributes to the remodeling of the tumor immunosuppressive microenvironment (TIME) by regulating B cells, dendritic cells (DCs), macrophages, and Treg cells. Targeting the UP

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… FBXO38: FBXO38, a component of the SCF (Skp1-Cullin-F-box) complex, specifically targets the Lys233 residue in the cytoplasmic domain of PD-1 for polyubiquitination ( 43 , 44 ). This polyubiquitination, typically Lys48-linked, signals for proteasome-dependent degradation of PD-1. … USP22 stabilizes CSN5 protein by deubiquitinating polyubiquitin chains, thereby enhancing PD-L1 expression. Knocking down USP22 can enhance T cell and NK cell activity, and when combined with ICIs, it significantly improves the therapeutic efficacy of ICIs ( 94 ). …

Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib.

One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulati

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… Compared with control and Bortezomib group, treated with Fluzoparib can enhance endogenous polyubiquitination level. … S3E showed that fluzoparib enhanced the level of endogenous protein polyubiquitination in H929 cells as bortezomib, and was equally effective against bortezomib-resistant MM cells. …

Сопротивление лекарствам в Множественной миеломе: опухоль-интринтические механизмы и микроокружающая среда костного мозга.

Множественная миелома (ММ) — злокачественное расстройство плазменных клеток, и, несмотря на значительные улучшения в прогнозе, полученные благодаря химиотерапии, иммунной терапии и автологической трансплантации стволовых клеток, у большинства пациентов в конечном счете возникает рецидив или рефракторное заболевание. Сопротивление лекарствам (DR) все чаще признается как динамическо развивающаяся экосистема, формируемая из опухоли-интенсивной пластичности и непрерывной реконструкцией микроокружающей среды костного мозга (BMME), а не как одно молекулярное повреждение. В настоящем обзоре резюмирую

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… Ubiquitination is a chain reaction; loss or inactivation of the chain‐elongating E2 prevents efficient polyubiquitin assembly even when IMiDs recruit substrates to CRBN, limiting degradation and blunting IMiD activity. … This leads to their polyubiquitination and subsequent proteasomal degradation, which downregulates the downstream IRF4–c‐MYC transcriptional axis, thereby suppressing survival signaling and triggering apoptosis in MM cells. …

RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and

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… (B) Inhibition of synoviolin 33 P-polyubiquitination by LS-101 and chemical structure of LS-101. (C) Inhibition of synoviolin 33 P-polyubiquitination by LS-102 and chemical structure of LS-102. …

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma.

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three protea

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… This process consists of 3 steps; polyubiquitination, deubiquitination and proteasomal degradation of the target protein ( 7 ). Proteins targeted by Ubiquitin-Proteasome Pathway (UPP) are initially tagged by polyubiquitin molecules through a series of enzymes. … The 19S regulatory unit is responsible for processing the polyubiquitin chains which ensures that only targeted proteins are degraded through the proteasome ( 7 ). …

Убиквитационное регулирование гликолитического фермента MCT4 в поощрении астроцитной реактивности во время нейроинфламмации.

Одним из гистопатологических признаков нервно-воспалительных заболеваний, таких, как множественный склероз (MS), является появление астроцитной реактивности. Накопление данных свидетельствует о том, что чрезмерный гликолиз может привести к астроцитной реактивности и способствовать нейроэнфламативным реакциям. Однако сложные механизмы, лежащие в основе метаболического перепрограммирования астроцитов в направлении гликолиза, остаются в значительной степени неизвестными. Здесь мы провели эксперименты in vitro с использованием первичных астроцитов и в vivo в экспериментальной аутоиммунной энцефало

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… Our findings indicated that TRIM7 overexpression significantly increased K48-linked polyubiquitination of MCT4, which typically leads to protein degradation (Fig.  5 E). Fig. 5 TRIM7 restricts MCT4-mediated proliferation and glycolysis of astrocyte via ubiquitination. … Apart from a study reporting that TRIM7 enhanced RACO-1 protein stability via K63-linked polyubiquitination [ 47 ], in most cases, TRIM7 attached a K48-linked polyubiquitin chain to its substrate and induced proteasome-directed protein degradation. …

The Transcription Axes ERK-Elk1, JNK-cJun, and JAK-STAT Promote Autophagy Activation and Proteasome Inhibitor Resistance in Prostate Cancer Cells.

The rapid emergence of resistance limits the application of proteasome inhibitors against solid tumors, despite their effectiveness in the treatment of hematological malignancies. Resistant phenotypes are complex and multifaceted, and, thus, the mechanisms involved have not been adequately described. In this study, a Bortezomib-resistant prostate cancer cell line is created by using the PC-3 cell as a prostate carcinoma model of high metastatic potential. The main biochemical differences and adaptations exhibited by the resistant cells revolve around apoptosis evasion, autophagy induction (fun

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… This was theorized as a response to the proteasome’s inability to process the polyubiquitinated protein load, instead of a crucial aspect of Bortezomib resistance. … It interacts with LC3 II and the polyubiquitinated protein, leading to the protein’s degradation [ 69 ]. …

Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.

The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the life of CML patients, and improved their prognosis. However, TKI resistance is still a major problem with CML patients, reducing the efficacy of treatment and their quality of life. TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance. Now, the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs. However, data have shown that these new drugs may cause serio

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… Polyubiquitin modification of K48 and K63 is the most studied. … The results of the mechanism-based study suggested that grancalcin induced the K63-linked polyubiquitination of TRAF6 and led to its dimerization. …

Discovery of a Promising Hydroxyamino-Piperidine HDAC6 Inhibitor via Integrated Virtual Screening and Experimental Validation in Multiple Myeloma.

Background: Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC isozyme characterized by two catalytic domains and a zinc finger ubiquitin-binding domain. It plays critical roles in various cellular processes, including protein degradation, autophagy, immune regulation, and cytoskeletal dynamics. Due to its multifunctional nature and overexpression in several cancer types, HDAC6 has emerged as a promising therapeutic target. Methods: In this study, we employed a ligand-based pharmacophore modeling approach using a structurally diverse set of known HDAC6 inhibitors. This was followed by th

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… Aggresomes form in response to the ectopic expression of various misfolded proteins and serve as central depots for aggregated, polyubiquitinated protein species, and HDAC6 plays a pivotal role in this pathway, being selectively involved in aggresome formation through its interaction with polyubiquitinated … Disruption of HDAC6 function impairs the delivery of these polyubiquitinated proteins to dynein, compromises aggresome assembly, and hampers the clearance of misfolded proteins from the cytoplasm. …