更新于：2024-11-01

USP5

更新于：2024-11-01

基本信息

别名

Deubiquitinating enzyme 5、isopeptidase T、IsoT

+ [6]

简介

Cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers. Involved in unanchored 'Lys-48'-linked polyubiquitin disassembly. Binds linear and 'Lys-63'-linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition.

关联

靶点

HDACs x USP5 x c-Myc

作用机制

HDAC抑制剂 [+2]

在研机构

Children's Cancer Institute Australia

原研机构

Children's Cancer Institute Australia

在研适应症

神经母细胞瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 USP5 相关的临床结果

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100 项与 USP5 相关的转化医学

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0 项与 USP5 相关的专利（医药）

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195

项与 USP5 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

P62 promotes FSH-induced antral follicle formation by directing degradation of ubiquitinated WT1

Article

作者: Wang, Jianbin ; Zhang, Tuo ; Zhu, Zijian ; Gao, Meng ; Xia, Guoliang ; Wang, Wenji ; Wang, Haibin ; Zheng, Wenying ; He, Meina ; Wang, Fengchao ; Zhao, Ting ; Qin, Shaogang ; Zhou, Bo ; Chen, Ziqi ; Han, Jun ; Wang, Chao ; Liu, Longping ; Zhang, Hua

AbstractIn females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitin‒proteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.

2024-10-01·Journal of Cachexia, Sarcopenia and Muscle

Hydrogen sulfide inhibits skeletal muscle ageing by up‐regulating autophagy through promoting deubiquitination of adenosine 5’‐monophosphate (AMP)‐activated protein kinase α1 via ubiquitin specific peptidase 5

Article

作者: E, Ya‐Qi ; Liang, Jin‐Long ; Yan, Qiu‐Yi ; Wu, Ren ; Yan, Guo‐Liang ; Wei, Zi‐Yi ; Li, Hong‐Zhu ; Yang, Jia‐He ; Jiao, Li‐Jie ; Gao, Jun

AbstractBackgroundHydrogen sulfide (H2S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H2S alleviates skeletal muscle ageing by regulating autophagy has not been reported.MethodsMice were administered 150 mg/kg/day of D‐galactose (D‐gal), and C2C12 myotubes were cultured in 20 g/L D‐gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H2S was quantified by the 7‐azido‐4‐methylcoumarin fluorescence probe. The proteins involved in the ubiquitin‐mediated degradation of AMPKα1 were detected by liquid chromatography tandem mass spectrometry (LC–MS/MS) and co‐immunoprecipitation (Co‐IP). S‐sulfhydration of USP5 was tested by a biotin‐switch assay. Associated proteins were analysed by western blot.ResultsNaHS was found to effectively restore the H2S content in both ageing gastrocnemius (+91.89%, P < 0.001) and C2C12 myotubes (+27.55%, P < 0.001). In comparison to the D‐gal group, NaHS was observed to increase the mean cross‐sectional area of muscle fibres (+44.91%, P < 0.001), to decrease the collagen volume fraction of gastrocnemius (−81.32%, P = 0.001) and to reduce the β‐galactosidase‐positive area of C2C12 myotubes (−28.74%, P < 0.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle‐specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: −31.73%, P = 0.008; MuRF1: −32.37%, P = 0.003; Cyclin D1: +45.34%, P = 0.010; p21: −25.53%, P = 0.022) and C2C12 myotubes (MAFbx: −16.38%, P < 0.001; MuRF1: −16.45%, P = 0.003; Cyclin D1: +40.23%, P < 0.001; p21: −35.85%, P = 0.026). The AMPKα1–ULK1 pathway was activated and autophagy was up‐regulated in NaHS‐treated gastrocnemius tissue (p‐AMPKα1: +61.61%, P = 0.018; AMPKα1: +30.64%, P = 0.010; p‐ULK1/ULK1: +85.87%, P = 0.005; p62: −29.07%, P < 0.001; Beclin1: +24.75%, P = 0.007; light chain 3 II/I [LC3 II/I]: +55.78%, P = 0.004) and C2C12 myotubes (p‐AMPKα1: +77.49%, P = 0.018; AMPKα1: +26.18%, P = 0.022; p‐ULK1/ULK1: +38.34%, P = 0.012; p62: −9.02%, P = 0.014; Beclin1: +13.36%, P < 0.001; LC3 II/I: +79.38%, P = 0.017; autophagy flux: +24.88%, P = 0.034) compared with the D‐gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN‐1604, and chloroquine could reverse its effects on ageing. LC–MS/MS and Co‐IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPKα1. Following the knockdown of USP5, the activation of AMPKα1 was decreased (p‐AMPKα1: −42.10%, P < 0.001; AMPKα1: −43.93%, P < 0.001), autophagy was inhibited (p‐ULK1/ULK1: −27.51, P = 0.001; p62: +36.00, P < 0.001; Beclin1: −22.15%, P < 0.001) and NaHS lost its ability to up‐regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, P < 0.001; C2C12 myotubes: +37.51%, P = 0.003) and S‐sulfhydration (+53.07%, P = 0.009) of USP5 and reduce the ubiquitination of AMPKα1.ConclusionsH2S promotes the deubiquitination of AMPKα1 by increasing the expression and S‐sulfhydration of USP5, thereby up‐regulating autophagy and alleviating skeletal muscle ageing.

2024-09-19·British journal of pharmacology

Contribution of T-type calcium channel isoforms to cold and mechanical sensitivity in naïve and oxaliplatin-treated mice of both sexes.

Article

作者: Snutch, Terrance P ; Hildebrand, Michael ; Santin, José Roberto ; Zamponi, Gerald W ; Souza, Ivana A ; Gadotti, Vinicius M ; David, Laurence S ; Antunes, Flavia T T ; Quintão, Nara Lins Meira ; Gandini, Maria A

BACKGROUND AND PURPOSEThe chemotherapy agent oxaliplatin can give rise to oxaliplatin-induced peripheral neuropathy (OIPN). Here, we investigated whether T-type calcium channels (Ca_v3) contribute to OIPN.EXPERIMENTAL APPROACHWe chronically treated mice with oxaliplatin and assessed pain responses and changes in expression of Ca_v3.2 calcium channels. We also tested the effects of T-type channel blockers on cold sensitivity in wild-type and Ca_v3.2 null mice.KEY RESULTSOxaliplatin treatment led to mechanical and cold hypersensitivity in male and female mice. Mechanical hypersensitivity persisted in Ca_v3.2 null mice of both sexes. Intraperitoneal or intrathecal delivery of pan T-type channel inhibitors attenuated mechanical hypersensitivity in wild-type but not Ca_v3.2 null mice. Remarkably cold hypersensitivity occurred in female but not male Ca_v3.2 null mice even without oxaliplatin treatment. Unexpectedly, intrathecal, intraplantar or intraperitoneal delivery of T-type channel inhibitors Z944 or TTA-P2 transiently induced cold hypersensitivity in both male and female wild-type mice. Acute knockdown of specific Ca_v3 isoforms revealed that the depletion of Ca_v3.1 in males and depletion of either Ca_v3.1 or Ca_v3.2 in females triggered cold hypersensitivity. Finally, reducing Ca_v3.2 expression by disrupting the interactions between Ca_v3.2 and the deubiquitinase USP5 with the small organic molecule II-2 reversed oxaliplatin-induced mechanical and cold hypersensitivity and importantly did not trigger cold allodynia.CONCLUSION AND IMPLICATIONSAltogether, our data indicate that T-type channels differentially contribute to the regulation of cold and mechanical hypersensitivity, and raise the possibility that T-type channel blockers could promote cold allodynia.