更新于：2024-11-01

USP19

更新于：2024-11-01

基本信息

别名

Deubiquitinating enzyme 19、KIAA0891、Ubiquitin carboxyl-terminal hydrolase 19

+ [6]

简介

Deubiquitinating enzyme that regulates the degradation of various proteins. Deubiquitinates and prevents proteasomal degradation of RNF123 which in turn stimulates CDKN1B ubiquitin-dependent degradation thereby playing a role in cell proliferation. Involved in decreased protein synthesis in atrophying skeletal muscle. Modulates transcription of major myofibrillar proteins. Also involved in turnover of endoplasmic-reticulum-associated degradation (ERAD) substrates. Regulates the stability of BIRC2/c-IAP1 and BIRC3/c-IAP2 by preventing their ubiquitination. Required for cells to mount an appropriate response to hypoxia and rescues HIF1A from degradation in a non-catalytic manner. Plays an important role in 17 beta-estradiol (E2)-inhibited myogenesis. Decreases the levels of ubiquitinated proteins during skeletal muscle formation and acts to repress myogenesis. Exhibits a preference towards 'Lys-63'-linked ubiquitin chains.

关联

项与 USP19 相关的药物

ADC-846

靶点

USP19

作用机制

USP19 inhibitors

在研机构

Almac Discovery Ltd.

原研机构

Almac Discovery Ltd.

在研适应症

恶病质

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 USP19 相关的临床结果

登录后查看更多信息

100 项与 USP19 相关的转化医学

登录后查看更多信息

0 项与 USP19 相关的专利（医药）

登录后查看更多信息

项与 USP19 相关的文献（医药）

2024-10-01·Molecular & Cellular Proteomics

Proteomic characterization of ubiquitin carboxyl-terminal hydrolase 19 deficient cells reveals a role for USP19 in secretion of lysosomal proteins

Article

作者: Ye, Yihong ; Lichtenthaler, Stefan F. ; Mueller, Stephan A ; Mueller, Stephan A. ; Scilabra, Simone D. ; Scilabra, Simone D ; Lo Pinto, Margot ; Lichtenthaler, Stefan F ; Bonelli, Simone

Ubiquitin carboxyl-terminal hydrolase 19 (USP19) is a unique deubiquitinase (DUB), characterized by multiple variants generated by alternative splicing. Several variants bear a C-terminal transmembrane domain that anchors them to the endoplasmic reticulum (ER). Other than regulating protein stability by preventing proteasome degradation, USP19 has been reported to rescue substrates from ER-associated protein degradation (ERAD) in a catalytic-independent manner, promote autophagy and address proteins to lysosomal degradation via endosomal microautophagy. USP19 has recently emerged as the protein responsible for the unconventional secretion of misfolded proteins including Parkinson's disease-associated protein α-synuclein. Despite mounting evidence that USP19 plays crucial roles in several biological processes, the underlying mechanisms are unclear due to lack of information on the physiological substrates of USP19. Herein, we used high-resolution quantitative proteomics to analyze changes in the secretome and cell proteome induced by loss of USP19 to identify proteins whose secretion or turnover is regulated by USP19. We found that ablation of USP19 induced significant proteomic alterations both in and out of the cell. Loss of USP19 impaired the release of several lysosomal proteins, including legumain (LGMN) and several cathepsins. In order to understand the underlaying mechanism, we dissected the USP19-regulated secretion of LGMN in several cell types. We found that LGMN was not a DUB substrate of USP19 and that its USP19-dependent release did not require their direct interaction. LGMN secretion occurred by a mechanism that involved the Golgi apparatus, autophagosome formation and lysosome function. This mechanism resembled the recently described "lysosomal exocytosis", by which lysosomal hydrolases are secreted, when ubiquitination of p62 is increased in cells lacking deubiquitinases such as USP15 and USP17. In conclusion, our proteomic characterization of USP19 has identified a collection of proteins in the secretome and within the cell that are regulated by USP19, which link USP19 to secretion of lysosomal proteins, including LGMN.

2024-08-01·Current Medical Science

USP19 Stabilizes TAK1 to Regulate High Glucose/Free Fatty Acid-induced Dysfunction in HK-2 Cells

Article

作者: Zhu, Yan-Ting ; Zhu, Yin-Na ; Yan, Xiao-Hui

OBJECTIVEObesity-induced kidney injury contributes to the development of diabetic nephropathy (DN). Here, we identified the functions of ubiquitin-specific peptidase 19 (USP19) in HK-2 cells exposed to a combination of high glucose (HG) and free fatty acid (FFA) and determined its association with TGF-beta-activated kinase 1 (TAK1).METHODSHK-2 cells were exposed to a combination of HG and FFA. USP19 mRNA expression was detected by quantitative RT-PCR (qRT-PCR), and protein analysis was performed by immunoblotting (IB). Cell growth was assessed by Cell Counting Kit-8 (CCK-8) viability and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Cell cycle distribution and apoptosis were detected by flow cytometry. The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation (Co-IP) assays and IB.RESULTSIn HG+FFA-challenged HK-2 cells, USP19 was highly expressed. USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells. Moreover, USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1 (PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species (ROS) generation in HK-2 cells. Mechanistically, USP19 stabilized the TAK1 protein through deubiquitination. Importantly, increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells.CONCLUSIONThe findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1, providing a potential therapeutic strategy for combating DN.

2024-08-01·Molecular Biotechnology

USP19 Negatively Regulates p53 and Promotes Cervical Cancer Progression

Article

作者: Singh, Vijai ; Suresh, Bharathi ; Tyagi, Apoorvi ; Chandrasekaran, Arun Pandian ; Antao, Ainsley Mike ; Sarodaya, Neha ; Karapurkar, Janardhan Keshav ; Kaushal, Kamini ; Ramakrishna, Suresh ; Colaco, Jencia Carminha ; Hong, Seok-Ho ; Haq, Saba ; Kim, Kye-Seong ; Das, Soumyadip

p53 is a tumor suppressor gene activated in response to cellular stressors that inhibits cell cycle progression and induces pro-apoptotic signaling. The protein level of p53 is well balanced by the action of several E3 ligases and deubiquitinating enzymes (DUBs). Several DUBs have been reported to negatively regulate and promote p53 degradation in tumors. In this study, we identified USP19 as a negative regulator of p53 protein level. We demonstrate a direct interaction between USP19 and p53 by pull down assay. The overexpression of USP19 promoted ubiquitination of p53 and reduced its protein half-life. We also demonstrate that CRISPR/Cas9-mediated knockout of USP19 in cervical cancer cells elevates p53 protein levels, resulting in reduced colony formation, cell migration, and cell invasion. Overall, our results indicate that USP19 negatively regulates p53 protein levels in cervical cancer progression.

项与 USP19 相关的新闻（医药）

2023-04-12

·生物谷

USP18是肌肉细胞分化和成熟的重要调节因子

肌肉退化是行动能力下降的标志。肌肉变性的特征是萎缩、脂肪浸润、纤维化和再生受损，这些都受到多种细胞机制的共同调节，其中泛素-蛋白酶体系统发挥着重要作用。肌肉退化是行动能力下降的标志。肌肉变性的特征是萎缩、脂肪浸润、纤维化和再生受损，这些都受到多种细胞机制的共同调节，其中泛素-蛋白酶体系统发挥着重要作用。肌肉被发现以泛素积累为特征，这伴随着几种DUB的表达和活性的改变。最近，USP19和USP1被发现与肌肉萎缩有关，也可能影响肌肉生成。肌发生是指在肌肉再生过程中，通过肌肉干细胞的增殖和随后的分化形成新的肌肉纤维。这一过程高度依赖于肌肉特异性调节因子的及时转换。已经发现USP7和USP10调节肌生成因子。总之，这表明DUBs可能有助于肌肉再生和退化。尽管肌肉退化在病理条件下有很大影响，但对100多个DUB在肌肉生物学方面的作用知之甚少。图片来源： https://doi.org/10.1038/s41419-023-05725-z 近日，来自莱顿大学的研究者们在Cell Death Dis.杂志上发表了题为“USP18 is an essential regulator of muscle cell differentiation and maturation”的文章，该研究结果表明，核泛素特异性蛋白酶18（USP18）是肌肉分化起始和维持的关键调节因子，独立于ISG15及其在ISG反应中的作用。研究者进行了基因筛选，以确定DUBs是肌肉细胞分化的潜在调节因子。令人惊讶的是，他们观察到USP18的缺失影响了肌肉细胞的分化。USP18耗竭首先刺激分化起始。后来，在分化过程中，USP18表达的缺失消除了肌管的维持。USP18酶功能通常通过从蛋白质底物中去除干扰素刺激的基因15（ISG15）来减弱免疫反应。然而，在肌肉细胞中，研究者发现USP18，尤其是核细胞，独立于ISG15和ISG反应调节分化。通过探索RNA表达谱和蛋白质网络的模式，研究者发现分化起始伴随着细胞周期基因网络的表达减少和肌源性转录因子的表达改变。USP18的缺失改变了钙通道基因网络，导致肌管中的钙流量减少。此外，研究者发现USP18蛋白质组中肌聚体蛋白表达的减少与工程肌肉模型中收缩力的减少一致。饥饿（无血清）诱导分化过程中USP18敲低的加速作用的机制图图片来源： https://doi.org/10.1038/s41419-023-05725-z 综上所述，本研究描述了USP18在肌发生中的一种新功能，该功能似乎独立于其在蛋白质脱ISGylation中的作用。USP18的去除阻止了人类肌肉细胞的增殖，并导致向加速分化的转变。当选择性USP18抑制剂可用时，它可能代表一种区分经典（催化）和非经典功能的途径，从而达到加速肌肉再生的目的。（生物谷 Bioon.com）参考文献 Cyriel Sebastiaan Olie et al. USP18 is an essential regulator of muscle cell differentiation and maturation. Cell Death Dis. 2023 Mar 31;14(3):231. doi: 10.1038/s41419-023-05725-z.