USP16

更新于：2025-05-07

基本信息

别名

Deubiquitinating enzyme 16、Ubiquitin carboxyl-terminal hydrolase 16、ubiquitin specific peptidase 16

+ [5]

简介

Specifically deubiquitinates 'Lys-120' of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator (PubMed:17914355). Deubiquitination of histone H2A is a prerequisite for subsequent phosphorylation at 'Ser-11' of histone H3 (H3S10ph), and is required for chromosome segregation when cells enter into mitosis (PubMed:17914355). In resting B- and T-lymphocytes, phosphorylation by AURKB leads to enhance its activity, thereby maintaining transcription in resting lymphocytes. Regulates Hox gene expression via histone H2A deubiquitination (PubMed:17914355). Prefers nucleosomal substrates (PubMed:17914355). Does not deubiquitinate histone H2B (PubMed:17914355). Also deubiquitinates non-histone proteins, such as ribosomal protein RPS27A: deubiquitination of monoubiquitinated RPS27A promotes maturation of the 40S ribosomal subunit (PubMed:32129764). Also mediates deubiquitination of tektin proteins (TEKT1, TEKT2, TEK3, TEKT4 and TEKT5), promoting their stability.

关联

100 项与 USP16 相关的临床结果

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100 项与 USP16 相关的转化医学

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0 项与 USP16 相关的专利（医药）

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项与 USP16 相关的文献（医药）

2025-04-01·Science China Life Sciences

Bacterial indole-3-propionic acid inhibits macrophage IL-1β production through targeting methionine metabolism

Article

作者: Ren, Wenkai ; Fu, Jian ; Gong, Aiyan ; Han, Ziyi

The gut microbiota plays key roles in host health by shaping the host immune responses through their metabolites, like indole derivatives from tryptophan. However, the direct role of these indole derivatives in macrophage fate decision and the underlying mechanism remains unknown. Here, we found that bacterial indole-3-propionic acid (IPA) downregulates interleukin-1beta (IL-1β) production in M1 macrophages through inhibition of nuclear factor-kappa B (NF-κB) signaling. Mechanistically, IPA binds specifically with methionine adenosyl-transferase 2A (MAT2A) to promote S-adenosylmethionine (SAM) synthesis, which facilitates the DNA methylation of ubiquitin-specific peptidase 16 (USP16, a deubiquitinase), and in turn promotes Toll-like receptor 4 (TLR4) ubiquitination and NF-κB inhibition. Furthermore, IPA administration attenuates sepsis in mouse models induced by lipopolysaccharides (LPS), showcasing its potential as a microbial-derived adjunct in alleviating inflammation. Collectively, our findings reveal a newly found microbial metabolite-immune system regulatory pathway mediated by IPA.

2024-12-01·Alzheimer's & Dementia

Identification of USP16 cryo‐EM protein structure and development of a small molecule inhibitor to restore compromised neural stem cell regeneration in a mouse Alzheimer’s model

Article

作者: Fernandez, Daniel ; Qian, Dalong ; Reinitz, Felicia ; Chen, Elizabeth Y. ; Clarke, Michael F. ; Igboabuchi, Francie I. ; Alford, Vincent M. ; Gottlieb, Sydney ; Djomehri, Sabra I. ; Ho, William Hai Dang ; Singal, Bharti ; Kuo, Angera H. ; Montabana, Elizabeth ; Qi, Zhen ; Chung, Grace Yuna

AbstractBackgroundHallmark pathologies of Alzheimer’s Disease (AD) include the accumulation of both extracellular amyloid and intracellular tau proteins. While a significant body of knowledge exists surrounding the role of the protein aggregates in the context of AD, research supporting these as targets for therapeutic development have yielded inconsistent findings. One significant barrier is the inability to restore cognitive function despite the successful clearance of these proteins. In our recently published paper, we discuss a novel target for AD, USP16, which has been shown to promote ubiquitination of histones allowing for transcription of CDKN2A, a cell cycle regulator. We demonstrated that knockdown of USP16 improved neurosphere initiating capacity in mouse neural stem cells. Moreover, reduction of USP16 expression via heterozygosity resulted in improved cognition in 12‐month‐old mice. From these findings, our lab aims to identify the full‐length protein structure of USP16 using cryogenic electron microscopy (cryo‐EM) and develop a small molecule drug to inhibit its activity for end‐use as a viable AD therapeutic option.MethodsTruncated regions corresponding to the active and zinc‐finger (ZnF) domains of USP16 were expressed in both HEK293T and SF9 cells. Whole cell lysates were purified using affinity chromatography and identity was verified using Western blot. The purified protein products were submitted for cryo‐EM to determine their respective structures. Focusing on the ZnF domain, we utilized both a previously published proton NMR‐derived structure as well as AlphaFold‐predicted USP16 protein structure to serve as model scaffolding onto which we could perform in silico small molecule drug screening. Libraries were obtained from Schrodinger, MilliporeSigma, Emanine, MolPort, Thermo Fisher, MedChemExpress, Life Chemicals, ChemDiv, and Mcule.ResultsChromatogram from affinity chromatography and Western blot imaging together indicate successful isolation of truncated USP16 domains expressed in HEK293T and SF9 cells. Preliminary findings from cryo‐EM on the WT SF9 construct recapitulates the major domains predicted by AlphaFold. Over 9.5 million small molecule hit interactions against the ZnF domain have been identified.ConclusionCryo‐EM was successful in generating a course model of USP16. In silico protein modeling and drug screening was able to identify potential ligands against the ZnF domain of USP16.

2024-11-01·Nature Structural & Molecular Biology

Structural and mechanistic basis for nucleosomal H2AK119 deubiquitination by single-subunit deubiquitinase USP16

Article

作者: Deng, Zhiheng ; Li, Jia-Bin ; Liu, Lei ; He, Zaozhen ; Chu, Guo-Chao ; Pan, Man ; Shi, Qiang ; Ai, Huasong ; Tong, Zebin

Epigenetic regulators have a crucial effect on gene expression based on their manipulation of histone modifications. Histone H2AK119 monoubiquitination (H2AK119Ub), a well-established hallmark in transcription repression, is dynamically regulated by the opposing activities of Polycomb repressive complex 1 (PRC1) and nucleosome deubiquitinases including the primary human USP16 and Polycomb repressive deubiquitinase (PR-DUB) complex. Recently, the catalytic mechanism for the multi-subunit PR-DUB complex has been described, but how the single-subunit USP16 recognizes the H2AK119Ub nucleosome and cleaves the ubiquitin (Ub) remains unknown. Here we report the cryo-EM structure of USP16-H2AK119Ub nucleosome complex, which unveils a fundamentally distinct mode of H2AK119Ub deubiquitination compared to PR-DUB, encompassing the nucleosome recognition pattern independent of the H2A-H2B acidic patch and the conformational heterogeneity in the Ub motif and the histone H2A C-terminal tail. Our work highlights the mechanism diversity of H2AK119Ub deubiquitination and provides a structural framework for understanding the disease-causing mutations of USP16.

项与 USP16 相关的新闻（医药）

2024-06-28

·生物探索

NSMB | 刘磊/潘漫合作揭示单亚基去泛素化酶USP16对核小体H2AK119Ub进行去泛素化的机制

引言组蛋白H2AK119位点单泛素化修饰（H2AK119Ub）是调节基因转录、DNA损伤修复和高阶染色质结构的关键表观遗传学标志。H2AK119Ub由泛素E3连接酶PRC1写入，并被USP3, USP12, USP16, USP21, USP22, USP46, PR-DUB and Mysm1等多种去泛素化酶擦除。其中，USP16是最早在2007年被鉴定到的H2AK119Ub核小体去泛素酶。USP16对H2AK119Ub的擦除在细胞周期M期进展、基因表达、干细胞自我更新和细胞衰老中至关重要。在阿尔茨海默症中，抑制USP16表达能逆转干细胞衰老和记忆丧失【1】。此外，基因定位在二十一号染色体的USP16在唐氏综合征（也称“21-三体综合征”）患者体内剂量依赖地过表达，导致干细胞缺陷等障碍【2,3】。尽管USP16具有很重要的生理与病理功能，但我们尚不清楚USP16催化H2AK119Ub核小体去泛素化的机制细节。近期报道的H2AK119Ub被异源二聚体去泛素化酶PR-DUB选择性擦除的机制显示PR-DUB催化亚基BAP1和辅因子ASXL协同识别核小体H2A-H2B酸性区域、核小体DNA SHL 0和SHL 6，将BAP1的活性中心靶向H2AK119Ub的异肽键，进而切割泛素【4,5】。然而，USP16与PR-DUB分属不同的去泛素化酶家族（USP家族与UCH家族），且USP16以单亚基形式独立擦除H2AK119ub（BAP1需要ASXL激活），表明USP16通过一种独特的识别和催化机制去泛素化H2AK119Ub核小体。 2024年6月25日，清华大学化学系刘磊团队和上海交通大学潘漫团队在Nature Structural & Molecular Biology在线发表Structural and mechanistic basis for nucleosomal H2AK119 deubiquitination by single-subunit deubiquitinase USP16的研究文章，揭示了人源单亚基去泛素化酶USP16以一种不依赖于核小体酸性区域的独特模式识别和去泛素化H2AK119Ub核小体，展现出与PR-DUB完全不同的H2AK119Ub去泛素化机制。本研究中，作者首先通过本团队2011年发展的多肽合成领域广泛使用的多肽酰肼法【6】、通过四片段分割法化学合成了具有天然异肽键链接的H2AK119Ub组蛋白（图1），并与其它三种核心组蛋白（H2B、H3、H4）组装成八聚体，随后缠绕601序列的DNA组装成H2A K119位点精准泛素化修饰的核小体。体外去泛素化实验表明，USP16在H2AK119Ub核小体底物而非组蛋白八聚体底物上具有泛素切割活性，表明USP16行使功能依赖完整的核小体结构。图1. 天然异肽键的H2AK119Ub组蛋白的化学合成路线【7】（Credit: Nature Structural & Molecular Biology）接着，为构建稳定酶-底物复合物，作者通过二溴丙酮方法合成了H2AK119Ub模拟物样品（图2）【8】，将泛素的羧基末端与H2A K119C的侧链通过烷基化反应连接起来，该链接形式可以耐受去泛素化酶的水解切割。图2. 异肽键不可水解的H2AK119Ub组蛋白的化学合成【8】（Credit: Nature Structural & Molecular Biology）随后作者将该不可水解的H2AK119Ub组蛋白组装成核小体，与人源全长USP16蛋白组装复合物，并通过冷冻电镜解析了整体分辨率为3.05 Å的1:1结合比例的复合物结构。在该结构中，USP16与H2AK119Ub核小体的相互作用主要分为三个部分：1) USP16的碱性残基R755和K272/K273分别识别核小体SHL 6.5和SHL 0 DNA；2) USP16与组蛋白H2A羧基末端尾巴和H2B羧基末端螺旋相互作用；3) USP16识别泛素分子上的L8、I36、I44和L71/L73互作热点区域。令人意外的是，USP16不与核小体上的染色质互作热点区域——H2A/H2B酸性区域产生相互作用。综上，这项研究揭示了单亚基去泛素化酶USP16擦除H2AK119Ub修饰的独特机制，强调了H2AK119Ub去泛素化机制的多样性，为理解USP16的疾病相关突变提供了结构框架。向期刊提交的封面概念图：核小体H2AK119Ub擦除模式的多样性，后方的起钉锤（PR-DUB）需要以木板（核小体H2A/H2B酸性区域）为支点拔出钉子（H2AK119Ub）；前方的钳子（USP16）不需要木板支撑即可拔出钉子（H2AK119Ub）（Credit: Nature Structural & Molecular Biology）参考文献 https://www.nature.com/articles/d41591-024-00013-5 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

蛋白降解靶向嵌合体临床结果临床1期

2022-10-06

·Science Daily

Scientists identify promising therapeutic target for incurable brain cancer

Researchers have discovered a cellular partnership that drives the growth of deadly brain tumors and could potentially serve as a novel target for disease treatment. A new study has uncovered a previously unknown genetic process that could inform the development of novel treatment options for GBM. Researchers at VCU Massey Cancer Center discovered a cellular partnership that drives the growth of deadly brain tumors and could potentially serve as a novel target for disease treatment. Gliomas are any cancer that start in the glial cells of the nervous system and account for nearly one-third of all brain tumors. The most aggressive type of glioma is called glioblastoma (GBM), which affects the brain and is virtually incurable. A new study -- published this week in Science Advances -- uncovered a previously unknown genetic process that could inform the development of novel treatment options for GBM. The epidermal growth factor receptor (EGFR) signaling pathway has previously been shown to be highly active in the majority of GBMs. Signaling pathways are like a cellular chain-of-command through which a string of proteins is triggered in a sequence to stimulate a specific cell function. The irregular activation of certain pathways can often lead to the development of disease, including cancer. "Dysregulated EGFR signaling is associated with worse outcomes and increased resistance to traditional therapies in GBM patients; thus, targeting EGFR has been regarded as a promising therapeutic strategy," said study author Suyun Huang, M.D., Ph.D., the Paul M. Corman, M.D., Chair in Cancer Research and member of the Cancer Biology research program at Massey. "However, the underlying cellular processes through which EGFR contributes to tumor growth are largely unknown." Previous research indicates that the EGFR pathway obstructs a natural process through which cells stop dividing called senescence, a mechanism that is critical in stunting the growth and spread of cancer cells. Blocking the function of the EGFR pathway promotes senescence and helps prohibit tumor growth. Through this new study, Huang and her research team demonstrated that a specific protein called ubiquitin-specific protease 16 (USP16) regulates senescence and mitigates the growth of glioma cells. They also identified a separate strand of long non-coding RNA -- molecules that control gene activity -- called lncEPAT that is activated through EGFR and is highly functional in GBM. Huang's findings suggest that lncEPAT acts as a genetic moderator allowing for EGFR to escape the antitumor role of USP16 and fuel cancer progression. In preclinical models, Huang found that the depletion of lncEPAT increased the activity of USP16 and stifled GBM cell growth. "We have compelling evidence that lncEPAT's cancer-driving function in GBM is dependent on the inactivation of the USP16 protein," said Huang, professor in the Department of Human and Molecular Genetics at the VCU School of Medicine. "EGFR-induced, overexpressed lncEPAT provides a promising new target for pro-senescence treatment for GBM." Huang collaborated on this study with Massey research members Jinze Liu, Ph.D., and Hengbin Wang, Ph.D.; Runping Fang, Ph.D., Linlin Li, Ph.D., Peng Li, M.D., and Hope Richard, M.D., Ph.D., of the VCU School of Medicine; Yiwen Chen, Ph.D., Li Ma, Ph.D., Longqiang Wang, Ph.D., Yanjun Wei, Ph.D., and Aldong Zhou, Ph.D., of MD Anderson Cancer Center; Feng Liu, Ph.D., of the Ludwig Institute for Cancer Research; and Sicong Zhang, Ph.D., of The Rockefeller University.

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