Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes
Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes
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DOI：
10.7554/elife.72879
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发表时间：
2022-06-23
期刊：
影响因子：
7.7
通讯作者：
Sorger PK
中科院分区：
文献类型：
--
作者：
Doherty LM;Mills CE;Boswell SA;Liu X;Hoyt CT;Gyori B;Buhrlage SJ;Sorger PK
脱泛素化酶(DUB)是一种从蛋白质中去除泛素结合物从而调节蛋白质周转的蛋白酶，其中约100种存在于人类细胞中。它们参与了广泛的细胞活动，是癌症和其他疾病的新兴治疗靶点。针对USP1和USP30的药物正在分别用于癌症和肾脏疾病的临床开发中。然而，大多数受DUBS调控的底物和途径仍然未知，阻碍了将特定酶优先用于研究和药物开发的努力。为了收集DUB活性、相互依赖的基因和底物的知识库，我们使用CRISPR文库和抑制剂进行了有针对性的实验，并对功能基因组数据库进行了系统的挖掘。对依赖图、连接图、癌细胞系百科全书和多个蛋白质-蛋白质相互作用数据库的分析得出了关于Dub功能的具体假设，其中一个子集在后续实验中得到了证实。本文中的数据可以在新开发的DUB门户网站上在线浏览，并有望提高对DUB家族以及不完全特征的DUB的活动(例如USPL1和USP32)以及那些已经针对癌症治疗的研究(例如USP14、UCHL5和USP7)的DUB的理解。
Deubiquitinating enzymes (DUBs), ~100 of which are found in human cells, are proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. They are involved in a wide range of cellular activities and are emerging therapeutic targets for cancer and other diseases. Drugs targeting USP1 and USP30 are in clinical development for cancer and kidney disease respectively. However, the majority of substrates and pathways regulated by DUBs remain unknown, impeding efforts to prioritize specific enzymes for research and drug development. To assemble a knowledgebase of DUB activities, co-dependent genes, and substrates, we combined targeted experiments using CRISPR libraries and inhibitors with systematic mining of functional genomic databases. Analysis of the Dependency Map, Connectivity Map, Cancer Cell Line Encyclopedia, and multiple protein-protein interaction databases yielded specific hypotheses about DUB function, a subset of which were confirmed in follow-on experiments. The data in this paper are browsable online in a newly developed DUB Portal and promise to improve understanding of DUBs as a family as well as the activities of incompletely characterized DUBs (e.g. USPL1 and USP32) and those already targeted with investigational cancer therapeutics (e.g. USP14, UCHL5, and USP7).