The function and regulation of OTU deubiquitinases
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REVIEW
The function and regulation of OTU deubiquitinases Jiansen Du1, Lin Fu1, Yingli Sui1, Lingqiang Zhang (
✉)2,3
1
Institute of Chronic Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao 266000, China; 2State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; 3Peixian People’s Hospital, Xuzhou 221600, China
© The Author(s) 2019. This article is published with open access at link.springer.com and journal.hep.com.cn 2019
Abstract Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including cell division, immune responses, and apoptosis. Ubiquitin-mediated control over these processes can be reversed by deubiquitinases (DUBs), which remove ubiquitin from target proteins and depolymerize polyubiquitin chains. Recently, much progress has been made in the DUBs. In humans, the ovarian tumor protease (OTU) subfamily of DUBs includes 16 members, most of which mediate cell signaling cascades. These OTUs show great variation in structure and function, which display a series of mechanistic features. In this review, we provide a comprehensive analysis of current progress in character, structure and function of OTUs, such as the substrate specificity and catalytic activity regulation. Then we discuss the relationship between some diseases and OTUs. Finally, we summarize the structure of viral OTUs and their function in immune escape and viral survival. Despite the challenges, OTUs might provide new therapeutic targets, due to their involvement in key regulatory processes. Keywords
ubiquitin; OTU deubiquitinases; structure; function; regulation
Introduction Protein ubiquitination is a reversible post-translational modification with key functions in regulating many cellular processes [1]. Ubiquitin is conjugated primarily to lysine and sometimes methionine of target proteins in a cascade of reactions catalyzed by the ubiquitin-activating enzyme (E1), the ubiquitin-conjugating enzyme (E2), and the ubiquitin-ligating enzyme (E3). This process can be reversed by deubiquitinases (DUBs) that cleave ubiquitin off the substrate protein. The equilibrium between ubiquitin conjugation and removal is important and tightly regulated. Its disruption is related to a number of human diseases including inflammatory, neurodegenerative, and metabolic disorders, as well as cancer [2]. The human genome encodes roughly 100 DUBs that fall into seven structural classes: ubiquitin-specific proteases (USPs), ovarian tumor proteases (OTUs), Machado-Joseph domain-containing proteases (MJDs), ubiquitin C-terminal hydrolases (UCHs), MINDYs (motif-interacting with ubiquitin containing proteases), ZUP1 (zinc finger containing ubiquitin peptidase 1) and JAMM/MPN domain-
Received August 3, 2019; accepted October 31, 2019 Correspondence: Lingqiang Zhang, [email protected]
associated Zn-dependent metalloproteases (JAMMs). The subfamily of OTUs has emerged as regulators of important signaling cascades, such
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