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Deubiquitinase USP4 suppresses antitumor immunity by inhibiting IRF3 activation and tumor cell-intrinsic interferon response in colorectal cancer.

Despite the approval of immune checkpoint blockade (ICB) therapy for various tumor types, its effectiveness is limited to only approximately … mpedes the nuclear localization of interferon regulator Factor 3 (IRF3) by deubiquitinating the K63-polyubiquitin chain of TRAF6 and IRF3. Knockdown of USP4 enhances the infiltration of T cells in CRC tumors and overcomes ICB resistance in an MC38 syngeneic mouse model. Moreover, published datasets revealed that patients showing higher USP4 expression exhibited …

Трансгенные рефракторные линии Aedes aegypti устойчивы к множественным серотипам вируса денге.

Районы, где вирус денге (DENV) является эндемичным, быстро расширились, отчасти под воздействием глобального распространения видов аедес, которые выступают в качестве переносчиков болезней. ДЕНВ реплицируется в комаровом мешке и распространяется в слюнных железах комара для усиления. Таким образом, блокирование вирусной инфекции или воспроизведение в тканях комаров может стать эффективной стратегией сокращения числа случаев передачи DENV людям. Здесь мы использовали транспосасу Mos1 для создания линии Aedes aegypti, которая выражает специфические по вирусу miRNA шпильки волос, способные блокир

Совпадение в аннотации оригинала
The areas where dengue virus (DENV) is endemic have expanded rapidly, driven in part by the global spread of Aedes species, which act as dis … cation. These microRNA are driven by the blood-meal-inducible carboxypeptidase A promoter or by the polyubiquitin promoter. The transgenic mosquitoes exhibited significantly lower infection rates and viral titers for most DENV serotypes 7 days after receiving an infectious blood meal. The treatment was also effective at day 14 post infection after a second bloo …

Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease.

Gaucher disease (GD), a sphingolipidosis characterized by impaired activity of the lysosomal enzyme glucocerebrosidase (GCase), results from … motes the accumulation of mutant GCase in aggresome-like structures and is involved in K48-mediated polyubiquitination of GCase mutants, indicating its function as its E3 ligase. We suggest that involvement of parkin in the degradation of mutant GCase explains the concurrence of GD and PD.

VHL suppresses UBE3B-mediated breast tumor growth and metastasis.

Protein homeostasis is predominantly governed through post-translational modification (PTM). UBE3B, identified as an oncoprotein, exhibits elevated protein levels in breast cancer. However, the impact of PTM on UBE3B remains unexplored. In this study, we show that VHL is a bona fide E3 ligase for UBE3B. Mechanistically, VHL directly binds to UBE3B, facilitating its lysine 48 (K48)-linked polyubiquitination at K286 and K427 in a prolyl hydroxylase (PHD)-independent manner. Consequently, this promotes the proteasomal degradation of UBE3B. The K286/427R mutation of UBE3B dramatically abolishes th…

TRIP suppresses cell proliferation and invasion in choroidal melanoma via promoting the proteasomal degradation of Twist1.

Choroidal melanoma (CM) remains the most prevalent form of intraocular malignancy, and the prognosis of affected patients is poor. While the … s are observed following TRIP knockdown. We further determined that TRIP is able to promote the K48-polyubiquitination of EMT-associated transcription factor Twist-related protein 1, thereby suppressing EMT progression. Together, our results suggest that TRIP plays an important role in regulating the progression of CM and that it may therefore be an important t …

Why is early-onset atrial fibrillation uncommon in patients with Duchenne muscular dystrophy? Insights from the mdx mouse.

AIMS: A reduction in both dystrophin and neuronal nitric oxide synthase (NOS1) secondary to microRNA-31 (miR-31) up-regulation contributes t … os1 transcript levels (exons 1-2 by quantitative polymerase chain reaction) and an increase in NOS1 polyubiquitination [assessed using tandem polyubiquitination pulldowns; P < 0.05 vs. wild type (WT)]. Neither the up-regulation of miR-31 nor the substantial reduction in NOS activity observed in the skeletal muscle was present in the atrial tissue of mdx mice. A …

Saikosaponin F ameliorates depression-associated dry eye disease by inhibiting TRIM8-induced TAK1 ubiquitination.

AIMS: Saikosaponin F (SsF) is one of the major active ingredients of Radix Bupleuri, an herb widely used in the treatment of depression. Stu … d dry eye model mice. SsF treatment downregulated TAK1 expression and TRIM8-induced K63-linked TAK1 polyubiquitination, while inhibiting the activation of NF-κB and MAPK (P38) inflammatory pathways and microglial expression. In addition, selective inhibition of TAK1 expression ameliorated depression-associated dry eye disease, while overexpression of TRIM8 atte …

OTUD6B-mediated K48 deubiquitination of FXR1 forms a positive feedback loop activating MEK2/ERK signaling in colorectal cancer liver metastasis.

Liver metastasis remains a major cause of mortality in patients with colorectal cancer (CRC). Here, we identify OTUD6B, a deubiquitinating enzyme of the OTU family, as a key driver of CRC liver metastasis. OTUD6B is upregulated in metastatic CRC tissues and is correlated with poor prognosis. Functionally, OTUD6B promotes CRC cell proliferation, migration, and invasion in vitro and enhances tumor growth and liver metastasis in vivo. Mechanistically, OTUD6B binds the KH domain of fragile X-related protein 1 (FXR1) via its N-terminal region and stabilizes FXR1 by removing K48-linked polyubiquitin…

Selective Modulation of OTUB1 Noncanonical Function via a bioPhosTAC Strategy.

OTUB1 is a canonical deubiquitinating enzyme that hydrolyzes K48-linked polyubiquitin chains as well as a regulator of several noncanonical pathways controlled by site-specific post-translational modifications. Phosphorylation at tyrosine 26 (Y26) of OTUB1 recently emerged as a key regulatory switch that stabilizes Raptor (central component of mTORC1), thereby enhancing mTORC1 activity and influencing cell growth and metabolism. Selective modulation of Y26 phosphorylation offers an opportunity to elucidate the noncanonical roles of OTUB1 without perturbing its catalytic activity. However, gene…

The TaLYK5-TaDSK2a module serves as a molecular switch between plant growth and immunity during fungal attack.

Plants are constantly challenged by pathogenic microorganisms that threaten growth and survival. While the individual signaling pathways inv … on by Pst, TaAKR2A does not initiate ROS signaling and immune responses and TaDSK2a associates with polyubiquitin chains on TaLYK5 to mediate its degradation, suppress TaLYK5-mediated plant defense. Meanwhile, TaDSK2a regulates gibberellin (GA) accumulation to promote plant growth, possibly by accelerating the degradation of TaEUI, a GA-deactivating enzyme. The …

S100A9 modulates USP7-mediated stabilization of NCOA4 to promote ferroptosis in sepsis-associated acute lung injury.

Sepsis-associated acute lung injury (SALI) is driven by dysregulated macrophage activation; however, mechanisms linking innate immune signal … as an intracellular scaffold, recruiting the deubiquitinase USP7 to NCOA4. USP7 cleaves K63-linked polyubiquitin chains at NCOA4 residues K42 and K181, preventing autophagic degradation and sustaining ferritin catabolism, iron release, and lipid peroxidation. Molecular docking reveals S100A9 optimally positions USP7 near NCOA4 K181 for site-specific deubiquiti …

Ubiquitin-specific peptidase 10 promotes renal interstitial fibrosis progression through deubiquitinating and stabilizing P53 protein.

Renal interstitial fibrosis is the main factor determining chronic kidney disease (CKD) progression, and renal tubular epithelial cells are … ion. Additionally, our results revealed that USP10 directly binds to P53 and removes the K48-linked polyubiquitin chains from P53, thereby affecting its ubiquitination, stability, and nuclear translocation, which subsequently leads to the upregulation of P21 and promotes fibrotic gene expression in injured renal tubular epithelial cells, ultimately exacerbating …

Targeting the ubiquitin-proteasome pathway in systemic lupus erythematosus.

INTRODUCTION: The ubiquitin-proteasome system (UPS) is the major non-lysosomal mechanism for selective degradation of intracellular proteins that is essential for the regulation of cellular functions and survival. Modulation of the proteasomes and cereblon E3 ligase promotes degradation of polyubiquitin-tagged transcription factors and oncoproteins, leading to depletion of long-lived plasma cells, diminished autoantibody and interferon-α production, reduced T-cell polarization to the proinflammatory phenotypes and increased regulatory T-cell activity that are relevant to the therapy of systemi…

Deubiquitinase JOSD2 alleviates colitis by inhibiting inflammation via deubiquitination of IMPDH2 in macrophages.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which increases the incidence of colorect … terminal of inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) and preferentially cleaves K63-linked polyubiquitin chains at the K134 site, suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B (NF-κB) and inflammation in macrophages. It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane (AOM)/DSS-induce …

Deubiquitinating enzyme YOD1 deubiquitinates and destabilizes α-synuclein.

α-synuclein is one of the proteins involved in degenerative neuronal diseases such as Parkinson's disease (PD) or Lewy body dementia (LBD). … YOD1 directly interacts with α-synuclein and deubiquitinates K6-, K11-, K29-, K33-, and K63-linked polyubiquitin chains on α-synuclein. Furthermore, YOD1 destabilizes α-synuclein protein stability by upregulating NEDD4. Collectively, this suggests the possibility that YOD1 is potentially a new regulator in the NEDD4-α-synuclein pathway.

Reduced chronic restraint stress in mice overexpressing hyperactive proteasomes in the forebrain.

While chronic restraint stress (CRS) results in depression-like behaviors possibly through oxidative stress in the brain, its molecular etio … that the α3ΔN transgenic mice are resistant to CRS. The accumulation of ER stress markers, such as polyubiquitin conjugates and phospho-IRE1α, was also significantly delayed in the hippocampus of the mutants. Notably, α3ΔN mice exhibited little deficits in other behavioral tasks, suggesting that stress resilience is likely due to the degradation of misfolded p …

A two years longitudinal study of a transgenic Huntington disease monkey.

BACKGROUND: A two-year longitudinal study composed of morphometric MRI measures and cognitive behavioral evaluation was performed on a transgenic Huntington's disease (HD) monkey. rHD1, a transgenic HD monkey expressing exon 1 of the human gene encoding huntingtin (HTT) with 29 CAG repeats regulated by a human polyubiquitin C promoter was used together with four age-matched wild-type control monkeys. This is the first study on a primate model of human HD based on longitudinal clinical measurements. RESULTS: Changes in striatal and hippocampal volumes in rHD1 were observed with progressive imp…

Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis.

Patients with Wilson's disease (WD), Indian childhood cirrhosis (ICC), and idiopathic copper toxicosis (ICT) develop severe liver disease mo … rotein (RIP) with the atypical protein kinase C. On the other hand, p62 binds with high affinity to polyubiquitin and ubiquitinated proteins. In conclusion, p62 accumulation in WD, ICC, and ICT and deposition in MBs indicates a central role of protein misfolding induced by oxidative stress in copper-induced liver toxicity. By sequestering potentially harmful mi …

The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function.

MitoKATP is a channel of the inner mitochondrial membrane that controls mitochondrial K+ influx according to ATP availability. Recently, the … the skeletal muscle triggered overt mitochondrial dysfunction and energy default, increased protein polyubiquitination, aberrant autophagy flux, and induction of a stress response program. MITOK overexpressing muscles were therefore severely atrophic. Thus, the proper modulation of mitoKATP activity is required for the maintenance of skeletal muscle homeostasis …

USP10 promotes intrahepatic cholangiocarcinoma cell survival and stemness via SNAI1 deubiquitination.

Cancer cell stemness contributes significantly to intrahepatic cholangiocarcinoma (ICC) progression. However, the roles of deubiquitinating enzymes (DUBs) in ICC modulation are poorly understood. Ubiquitin specific peptidase 10 (USP10) was highly expressed in ICC spheres. The interaction between USP10 and snail family transcriptional repressor 1 (SNAI1) reduced the polyubiquitination of the SNAI1 protein and stabilized the SNAI1 protein. USP10 knockdown in RBE cells inhibited cell proliferation, promoted cell apoptosis and decreased the diameter of the formed spheres and the expression levels …