TRIP13 Promotes the Expansion and Immunosuppression of CD4+Foxp3+ Regulatory T Cells by Sustaining HAT1 Stability

However, the precise mechanisms underlying TNF-TNFR2 pathway-mediated Treg proliferation remain to be fully elucidated. In this study, using RNA-seq profiling of TNFR2+ and TNFR2-deficient Treg cells, we identified that Trip13 is required for promoting TNF-TNFR2 pathway-mediated Treg expansion.

Mechanistically, TRIP13 inhibited UBE4A-mediated ubiquitination degradation of HAT1 by directly binding to HAT1, thereby competing with UBE4A and promoting Treg expansion. In addition, TRIP13’s ATPase activity was essential for its binding to HAT1, which promoted Treg expansion by increasing Foxp3 expression. In a mouse colitis model, TRIP13 overexpression markedly alleviated colon inflammation by enhancing Treg expansion, an effect that was reversed by HAT1 knockdown.