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Frontiers of Medicine

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Front. Med.    2018, Vol. 12 Issue (4) : 451-462    https://doi.org/10.1007/s11684-018-0651-y
REVIEW
Deubiquitinases as pivotal regulators of T cell functions
Xiao-Dong Yang1, Shao-Cong Sun2,3()
1. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2. Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA
3. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
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Abstract

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases (DUBs). DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.
Keywords deubiquitinase      ubiquitination      T cell activation      T cell differentiation      T cell tolerance     
Corresponding Author(s): Shao-Cong Sun   
Just Accepted Date: 02 July 2018   Online First Date: 30 July 2018    Issue Date: 03 September 2018
 Cite this article:   
Xiao-Dong Yang,Shao-Cong Sun. Deubiquitinases as pivotal regulators of T cell functions[J]. Front. Med., 2018, 12(4): 451-462.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0651-y
https://academic.hep.com.cn/fmd/EN/Y2018/V12/I4/451
Fig.1  Ubiquitination is a reversible reaction counter regulated by ubiquitinating enzymes and DUBs. (A) Ubiquitin conjugation onto a target protein is catalyzed by the sequential action of three ubiquitinating enzymes, E1, E2, and E3. Mammalian cells have 2 E1s, about 40 E2s, and more than 600 E3s. E3s mediate substrate recognition and determine the specificity of protein ubiquitination. Ubiquitination can occur via formation of different types of ubiquitin chains and regulate diverse cellular functions. Deubiquitinases (DUBs) cleave ubiquitin chains and deconjugate ubiquitin from substrates, thereby reversing the ubiquitination reaction. (B) DUBs are classified into six families, including five families of cysteine proteases and one family of metalloprotease.
Fig.2  DUBs regulating TCR signaling. DUBs regulate both TCR-proximal and downstream signaling events. Otud7b deconjugates non-degradative ubiquitin chains from Zap70 to prevent its association with a negative-regulatory phosphatase, Sts1 or Sts2, thereby promoting Zap70 activation. USP9X deubiquitinates Zap70 to prevent endosome sequestration of ubiquitinated Zap70. USP15 deubiquitinates and stabilizes MDM2, an E3 ligase mediating ubiquitination and proteolysis of an NFAT family member, NFATc2, and negatively regulating TCR signaling. Several DUBs, including A20, CYLD, and USP18, deconjugate K63-linked ubiquitin chains from the TAK1/IKK signaling complex to negatively regulate this signaling pathway.
Fig.3  DUBs involved in regulation of CD4+ T cell differentiation. DUBs may regulate CD4+ T cell differentiation through controlling cytokine production during the early phase of T cell activation or regulating the lineage transcription factors during the subsequent phase of differentiation. In addition to the polarizing cytokine IL-12, IFNg produced during T cell activation promotes Th1 differentiation. USP15 and USP18 attenuate Th1 differentiation by negatively regulating IFNg induction, whereas Otud7b has the opposite function. USP18 promotes Th17 cell differentiation by inhibiting production of the Th17-inhibitory cytokine IL-2. Several DUBs (USP4, USP15, and USP17) promote Th17 polarization by stabilizing or facilitating the function of RORgt, whereas DUBA inhibits Th17 polarization by promoting RORgt degradation. The DUB Trabid promotes Th1 and Th17 cell differentiation and inflammation by facilitating TLR-induced expression of the polarizing cytokines IL-12 and IL-23.
DUB Family Function Target References
CYLD USP Thymocyte development LCK, IKK [25, 27]
Survival of immature NKT cells IKK [29]
T cell activation TAK1, IKK [39, 40]
Treg development IKK, Smad7 [73, 75, 76]
USP4 USP Th17 differentiation RORgt [64]
USP7 USP Treg function Foxp3, Tip60 [79−81]
USP8 USP Thymocyte maturation CHMP5 [35, 36]
USP9X USP TCR signaling Bcl10 [48]
TCR signaling and central tolerance Zap70 [53, 54]
TCR signaling Themis [55]
USP10 USP Unknown T-bet [60]
USP15 USP T cell activation and differentiation MDM2 [49]
Th17 differentiation RORgt [65]
USP17 USP Th17 differentiation RORgt [63]
USP18 USP Th17 differentiation TAK1-TAB1 [41]
A20 OTU NKT cell differentiation MALT1 [33]
CD8 T cell activation NF-kB pathway [43, 44]
CD4 T cell survival RIPK3 [45]
T cell survival mTORC1 [46]
Cell-extrinsic regulation of Th1 and Th17 cell differentiation NF-kB pathway [68−70]
Treg development NF-kB pathway [77]
Otud7b OTU T cell activation and differentiation Zap70 [50]
DUBA OTU Th17 differentiation UBR5 [61]
Zranb1 OTU Cell-extrinsic regulation of Th1 and Th17 cell differentiation Jmjd2b [67]
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[1] Jiansen Du, Lin Fu, Yingli Sui, Lingqiang Zhang. The function and regulation of OTU deubiquitinases[J]. Front. Med., 2020, 14(5): 542-563.
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