Last update 01 Nov 2024

USP19

Last update 01 Nov 2024

Basic Info

Synonyms

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

+ [6]

Introduction

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.

Drugs associated with USP19

ADC-846

Target

USP19

Mechanism

USP19 inhibitors

Active Org.

Almac Discovery Ltd.

Originator Org.

Almac Discovery Ltd.

Active Indication

Cachexia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with USP19

100 Translational Medicine associated with USP19

0 Patents (Medical) associated with USP19

Literatures (Medical) associated with USP19

01 Oct 2024·Molecular & Cellular Proteomics

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

Article

Author: 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.

01 Aug 2024·Current Medical Science

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

Article

Author: 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.

01 Aug 2024·Molecular Biotechnology

USP19 Negatively Regulates p53 and Promotes Cervical Cancer Progression

Article

Author: 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.

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USP19

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