Fig. 2

DUBs regulate EAE by modulating TCR signaling. T cells are essential effector cells in EAE and their functions are critically dependent on TCR-induced signaling, which is fine-tuned by DUBs. OTUD7B inhibits K33 ubiquitination of Zap70 and thereby potentiates its phosphorylation by reducing the recruitment of Zap70 inhibitors Sts1 and Sts2, leading to increased T cell activation and Th1 differentiation. USP18 deubiquitinates TAK1 and inhibits its activity, resulting in reduced NF-κB and NFAT activation and subsequent IL-2 production. Since IL-2 suppresses Th17 polarization, Th17 differentiation is strongly enhanced by USP18. Upon intracellular calcium stimulation, the binding of NFAT with calcineurin is inhibited by K29 ubiquitination of calcineurin, which can be stripped by USP16. By enhancing NFAT-mediated gene transcription, USP16 contributes to both the maintenance and proliferation of T cells. In addition to gene transcription, activation of TCR leads to necroptosis of T cells by inducing formation of the RIPK1-RIPK3 complex, which is positively regulated by K63 ubiquitination of RIPK3. By deubiquitinating RIPK3, A20 disrupts the RIPK1-RIPK3 complex and protects T cells from necroptosis