USP19

更新于：2025-05-07

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

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100 项与 USP19 相关的转化医学

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0 项与 USP19 相关的专利（医药）

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项与 USP19 相关的文献（医药）

2025-04-01·Cell Death & Differentiation

USP19 potentiates autophagic cell death via inhibiting mTOR pathway through deubiquitinating NEK9 in pancreatic cancer

Article

作者: Dai, Shangnan ; Zhang, Kai ; Lu, Zipeng ; Chen, Jin ; Jiang, Kuirong ; Zhang, Jinfan ; Yin, Lingdi ; Miao, Yi ; Wang, Guangfu ; Xie, Kunxin ; Huang, Chenyu ; Gao, Yong ; Wang, Huijuan ; Lin, Fuye

The ubiquitin-specific protease (USP) family is the largest and most diverse deubiquitinase (DUBs) family and plays a significant role in maintaining cell homeostasis. Dysregulation of USPs has been associated with carcinogenesis of various tumors. We identified that USP19 was downregulated in pancreatic tumor tissues and forced expression of USP19 diminished tumorigenicity of pancreatic cancer. Mechanistically, USP19 directly interacts with and stabilized NEK9 via inhibiting K48-specific polyubiquitination process on NEK9 protein at K525 site through its USP domain. Moreover, NEK9 phosphorylates the regulatory associated protein of mTOR (Raptor) at Ser792 and links USP19 to the inhibition of mTORC1 signaling pathway, which further leads to autophagic cell death of pancreatic cancer cells. Inhibition of autophagy by Atg5 knockdown or lysosome inhibitor bafilomycin A1 abolished the decreased malignant phenotype of USP19- and NEK9-overexpressing cancer cells. Importantly, USP19 expression exhibits a positive correlation with NEK9 expression in clinical samples, and low USP19 or NEK9 expression is associated with a worse prognosis. This study revealed that USP19-mediated NEK9 deubiquitylation is a regulatory mechanism for mTORC1 inhibition and provides a therapeutic target for diseases involving mTORC1 dysregulation.

2025-04-01·Pharmacological Research

USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer

Article

作者: Shi, Feng ; Zhou, Hai-Meng ; Liu, Yi ; Li, Bo-Xin ; Dong, Ming-You ; Wang, Bai-Qi ; Zan, Bo-Jun ; Wei, Si-Yi ; Zhang, Yue ; Zhang, Xiao-Dong ; Du, Run-Lei ; Li, Guang-Jing ; Chen, Fei-Shan ; Gao, Meng

Colorectal cancer (CRC) is characterized by a highly immunosuppressive tumor microenvironment, which limits the effectiveness of current immunotherapies. Identifying strategies to overcome this resistance is critical for improving treatment outcomes. In this study, we discovered that USP19 plays a pivotal role in regulating T-cell-mediated antitumor immunity through a CRISPR/Cas9 sgRNA library screen and co-culture assays with activated T cells. We demonstrated that USP19 deficiency significantly enhances the susceptibility to T cell-mediated cytotoxicity in CRC cells, organoids, and mouse models. Transcriptomic sequencing (RNA-seq) revealed activation of the PD-1 pathway in tumor with USP19-deficiency cells. Mechanistic investigations revealed that USP19 directly stabilizes PD-L1 by binding to its intracellular domain and preventing its degradation via K48-linked ubiquitination and proteasomal pathways. Clinically, USP19 expression was found to be significantly elevated in CRC tissues and was positively associated with PD-L1 levels, advanced tumor grade, poor differentiation, and TP53 mutations, highlighting its potential as a biomarker for aggressive CRC. Importantly, in vivo experiments demonstrated that targeting USP19, in combination with αPD-L1 therapy, synergistically suppressed CRC progression. This combination not only reduced PD-L1 levels but also enhanced CD8⁺ T-cell activation and GzmB infiltration, resulting in robust antitumor effects. These findings establish USP19 as a key driver of immune evasion in CRC and suggest that targeting USP19 could enhance the efficacy of immunotherapy, providing a promising new avenue for CRC treatment.

2025-02-01·Advanced Science

Suppression of Hepatocyte Ferroptosis via USP19‐Mediated Deubiquitination of SLC7A11 in Ischemia‐Free Liver Transplantation

Article

作者: Stefan, Tullius G. ; Xu, Jinghong ; Cai, Changjie ; He, Xiaoshun ; Andrea, Schlegel ; Wang, Tielong ; Chen, Shirui ; Cui, Jun ; Zhang, Qi ; Nashan, Björn ; Lin, Yuan ; Pan, Hongyu ; Guo, Zhiyong ; Chen, Yichao ; Luo, Tao ; Zhou, Liang ; Zhao, Qiang ; Zhu, Jiaxing ; Liu, Di

AbstractIschemia‐free liver transplantation (IFLT) is developed as a novel clinical approach to avoid ischemia‐reperfusion injury (IRI). This study aims to identify the most distinguished programmed cell death pathway in grafts undergoing IFLT versus conventional liver transplantation (CLT) and to explore the underlying mechanism. Ferroptosis is the most distinct programmed cell death form between IFLT and CLT grafts. Among various cell death inhibitors, the ferroptosis inhibitor (Ferrostain‐1) is the most effective one to prevent hepatocytes from damage induced by oxygen deprivation/reoxygenation (OGD/R). Hepatocyte ferroptosis is significantly alleviated in IFLT versus CLT grafts in both human beings and pigs. Ubiquitination enzyme screening identifies augmented amounts of ubiquitin‐specific protease 19 (USP19) in IFLT versus CLT grafts. The upregulation of USP19 in the grafts is correlated with reduced pathological Suzuki's score, lower post‐transplant peak liver enzyme level, and less early allograft dysfunction in liver transplant recipients. USP19 overexpression mitigates post‐transplant liver injury in mice. Mechanistically, USP19 inhibits the degradation of solute carrier family 7 member 11 (SLC7A11) by removing its K63‐linked ubiquitin chains. Notably, USP19 overexpression reduces ferroptosis and IRI in a SLC7A11‐dependent manner in mice. Collectively, USP19‐mediated suppression of hepatocyte ferroptosis via deubiquitinating SLC7A11 is a key mechanism by which IFLT abrogates graft IRI.

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.

基因疗法临床研究