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Frontiers of Medicine

Front. Med.    2020, Vol. 14 Issue (5) : 542-563
The function and regulation of OTU deubiquitinases
Jiansen Du1, Lin Fu1, Yingli Sui1, Lingqiang Zhang2,3()
1. Institute of Chronic Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao 266000, China
2. State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
3. Peixian People’s Hospital, Xuzhou 221600, China
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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     
Corresponding Author(s): Lingqiang Zhang   
Just Accepted Date: 15 November 2019   Online First Date: 25 December 2019    Issue Date: 12 October 2020
 Cite this article:   
Jiansen Du,Lin Fu,Yingli Sui, et al. The function and regulation of OTU deubiquitinases[J]. Front. Med., 2020, 14(5): 542-563.
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Fig.1  Ubiquitin and UPS pathway. (A) The structure of ubiquitin (PDB: 1UBQ). The seven lysine, N-terminal methionine, and C-terminal diglycine are labeled. (B) The complexity of ubiquitin modifications. Monoubiquitin including seven lysines and one N-terminal methionine gives eight homotypic polyubiquitin chains. Heterotypic types contain mixed or branched linkage type. Also, the cross talk with other PTMs, such as SUMOylation, Neddylation, acetylation (Ac) and phosphorylation (P) enhances the complexity of ubiquitination. (C) A schematic model of UPS (Ub-proteasome system) pathway. Ubiquitin modification is an ATP-dependent process carried out by three classes of enzymes: E1, E2, and E3. The reversible process of ubiquitination is countered by DUBs action.
Fig.2  Structures of the catalytic domain of DUBs. (A) Structure of seven classes of DUBs. The active site cysteine or zinc is shown in magentas. OTUs (OTUB1, PDB: 2ZFG), USPs (USP7, PDB: 1NB8), UCHs (UCH-L3, PDB: 1UCH), MJDs (Ataxin-3, PDB: 3O65), MINDYs (MINDY1, PDB: 5JKN), ZUP1 (ZUP1, PDB: 6FGE), JAMMs (AfJAMM, PDB: 1R5X). (B) Basic nomenclature of OTU catalytic domain. The distal ubiquitin occupies the S1 site, and the proximal to the S1′ site. Sometimes, additional Ub binding sites, such as S2, S3, and S2′ are needed.
OTUs Cleavage specificity Substrates Biological functions PDB code References
OTUB1 K48 RNF128; USP8 (isoform 1); TRAF3; TRAF6; P53; UBE2N Regulate adaptive immunity, DNA damage repair, histone ubiquitination 2ZFY, 3VON, 4DDG, 4DDI, 4DHZ, 4I6L, 4LDT [3,4952]
OTUB2 K11/K48/K63 TRAF3; TRAF6; TRIM54 Regulate DNA damage repair, cancer metastasis 1TFF; 4FJV [39,49,50]
OTUD1 K63 SMAD7; YAP1; IRF3 Regulate interferon production; tumor suppressor 4BOP [5355]
OTUD2 (YOD1) K27/K29/K33 VCP; TRAF6 Regulate VCP/P97 and NF-kB signaling, Hippo pathway, and TGF-b pathway 4BOQ, 4BOS, 4BOZ [3,5658]
OTUD3 K6/K11/K48 PTEN; GRP78; TOP2A Regulate PTEN stability and suppress tumorigenesis; promotes lung tumorigenesis 4BOU [3,6,59]
OTUD4 K48/K63 MyD88; USP7; ALKBH2/3 Regulate inflammatory and innate immune response; DNA repair NA [60,61]
OTUD5 K48/K63, K11(in vitro) p53; TRAF3; PDCD5; Ku80 Regulate the innate immune system and stabilize p53 3PFY, 3TMO, 3TMP [7,62,63]
OTUD6A K11/K27/K29/K33 NA NA NA [3,64]
OTUD6B NA TIF4F Regulate cell growth and proliferation; proteasome assembly NA [3,65]
OTUD7A (Cezanne2) K11 TRAF6 Regulate HCC malignancy; regulate neurodevelopment NA [66,67]
OTUD7B (Cezanne1) K11/K48/K63 TRAF3; ZAP70; EGFR; Sox2 Regulate NF-kB signaling and TCR signaling; regulate T cell homeostasis; regulate cancer progression; stem cell differentiation 5LRU, 5LRV, 5LRW [6870]
A20 K11/K48/K63 TRAF6; FIP3; TNF; YWHAD Regulate NF-kB signaling, apoptosis and immunity 2VFJ, 3OJ3, 3OJ4, 3JZD, 3ZJF, 3ZJG, 5DQ6, 5LRX, 5V3B, 5V3P [8,40,7173]
Trabid (Zranb1) K29/K33/K63 APC; EZH2; Twist1 Regulate Wnt signaling; regulate cell morphology, cytoskeletal organization, cell migration 3ZRH, 5AF6, 4S1Z [44,74,75]
OTULIN (Fam105B) M1 RIPK2; RNF31; SHARPIN; DVL2 Regulate Wnt, NF-kB, TNF signaling, immunity response, inflammatory; sprouting angiogenesis 3ZNV, 3ZNX, 3ZNZ, 4KSJ, 4KSK, 4KSL, 4OYK, 4P0B, 5OE7, 6DRM, 6I9C [45,7678]
VCPIP (VCIP135) K11/K48 BoNT/A; P97 Regulate Golgi reassembly, mitotic cell cycle and endoplasmic reticulum membrane fusion; enhance duration of botulinum neurotoxin NA [79,80]
ALG13 NA NA Bifunctional enzyme with both glycosyltransferase and deubiquitinase activities NA [81]
Tab.1  Functional and structural information of OTUs
Fig.3  Catalytic reaction of OTUs. OTUs generally contain a catalytic triad composed of cysteine, histidine and an acidic residue. Upon diubiquitin binding, the deprotonated catalytic cysteine residue attacks the isopeptide linkage, forming a negatively charged tetrahedral intermediate. The proximal Ub releases from the catalytic center, and an acyl intermediate form. A water molecule triggers a deacylation reaction and then the distal Ub releases.
Fig.4  Phylogenetic tree and domain composition of human OTUs. (A) Phylogenetic tree of human OTUs. (B) Domain composition of human OTUs.
Fig.5  Structure of OTUs catalytic domain and diubiquitin/ubiquitin binding state. (A) OTUB subfamily (PDB: 2ZFY, 4DHZ, 4FJV); (B) OTUD subfamily (PDB: 4BOQ, 4BOZ, 4BOS); (C) A20 subfamily (PDB: 5LRU, 5LRV, 5LRW); (D) OTULIN subfamily (PDB: 3ZNV, 3ZNZ, 4KSK).
Fig.6  Structural insights into regulation mechanisms of OTUs activity. (A) Phosphoactivation modification of OTUD5 Ser177 residue (PDB: 3TMP). (B) Acetylation modification of A20 Cys103 residue (PDB: 5V3P). (C) Oxidation regulation of A20 Cys103 in reduced or oxidized station (PDB: 3ZJD, 3ZJE, 3ZJG). (D) Allosteric regulation of OTU7B and OTUB1. Allosteric regulation of OTUD7B by di-Ub binding and OTUB1 by di-Ub and UBC13 binding, the conformation changed remarkably are labeled in yellow cycle (PDB: 5LRW, 5LRV, 2ZFY, 4DHZ).
Fig.7  Structures of viral OTU domains and ISG15. (A−D) Crystal structures of (A) CCHFV viral OTU domain (PDB: 3PT2), (B) DUGV OTU domain (PDB: 4HXD), (C) EAV PLP2 (PDB: 4IUM), (D) TYMV OTU domain (PDB: 4A5U). (E) Crystal structure of ISG15 (PDB: 1Z2M), the N- and C-terminal UBL domain are labeled. (F) Crystal structure of CCHFV OTU-ISG15 complex (PDB: 3PHX).
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