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Review
. 2018 Aug;12(4):451-462.
doi: 10.1007/s11684-018-0651-y. Epub 2018 Jul 27.

Deubiquitinases as pivotal regulators of T cell functions

Xiao-Dong Yang  1 , Shao-Cong Sun  2   3
Affiliations
Review

Deubiquitinases as pivotal regulators of T cell functions

Xiao-Dong Yang et al. Front Med. 2018 Aug.

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: T cell activation; T cell differentiation; T cell tolerance; deubiquitinase; ubiquitination.

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Figures

Fig. 1
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
Fig. 2
DUBs regulating TCR signaling. DUBs regulate both TCR-proximal and downstream signaling events. Otud7b deconjugates nondegradative 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
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, IFNγ produced during T cell activation promotes Th1 differentiation. USP15 and USP18 attenuate Th1 differentiation by negatively regulating IFNγ 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 RORγτ, whereas DUBA inhibits Th17 polarization by promoting RORγτ 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.
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