biostudies-literatureHe TNational Natural Science Foundation of China (National Science Foundation of China)32https://www.ebi.ac.uk/biostudies/studies/S-EPMC12804696biostudies-literatureUnknown17(1)There is compelling evidence that TNF preferentially activates and expands CD4⁺Foxp3⁺ regulatory T cells (Tregs) through TNFR2. 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, TRIP13Cell death & diseaseTRIP13 promotes the expansion and immunosuppression of CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells by sustaining HAT1 stability.PMC12804696821005573203004882271256Yang HZhao LYFu ZJing SGao YJWang KZhao YFeng CTHe TZhao LYe SChou CKChen XYu YfalseTRIP13 promotes the expansion and immunosuppression of CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells by sustaining HAT1 stability.There is compelling evidence that TNF preferentially activates and expands CD4⁺Foxp3⁺ regulatory T cells (Tregs) through TNFR2. 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, TRIP132026-01-01T00:00:00Z2026 Jan2026-06-06T16:03:08.782Z2026-06-02T03:09:57.184ZS-EPMC128046964153526310.1038/s41419-025-08214-7