Fig. 2.

The roles of DUBs in modulating CD4⁺ T-cell differentiation. DUBs can regulate CD4⁺ T-cell differentiation into specific subsets. This not only highlights their roles in immunomodulation but also their implications in cancer immunotherapy. USP15 stabilizes MDM2 to enhance NFATc2 degradation, which downregulates IL-2 and IFN-γ and inhibits Th1 differentiation. Intriguingly, USP4 plays a dual role in CD4⁺ T-cell lineage commitment. On the one hand, it deubiquitinates RORγt to facilitate Th17 differentiation; on the other hand, it stabilizes IRF8 to augment the suppressive activities of Tregs, circumventing CD8⁺ T-cell function and infiltration. Both USP22 and USP7 induce Treg differentiation. USP22 counteracts E3 ligase Rnf20-mediated polyubiquitination of FoxP3; USP7 simultaneously deubiquitinate and stabilize FoxP3 and Tip60. These processes facilitate dimerization and acetylation of FoxP3, but are counteracted by USP1-mediated deubiquitination of TAZ. FoxP3: Forkhead box protein P3; IRF8: interferon regulatory factor 8; MDM2: murine double minute 2; NFATc2: nuclear factor of activated T cells c2; Rnf20: ring finger protein 20; RORγt: RAR-related orphan receptor-γ; Tip60: Tat-interactive protein 60