TRIM11 attenuates Treg cell differentiation by p62-selective autophagic degradation of AIM2

Ubiquitination is an important protein modification that regulates diverse biological processes, including CD4+ T cell differentiation and functions. However, the function of most E3 ubiquitin ligases in CD4+ T cell differentiation and CD4+ T cell-mediated pathological diseases remains unclear. In this study, we find that tripartite motif-containing motif 11 (TRIM11) specifically negatively regulates regulatory T (Treg) cell differentiation in CD4+ T cells and promotes autoimmune disease development in an AIM2-dependent manner. Mechanistically, TRIM11 interacts with absent in melanoma 2 (AIM2) and promotes the selective autophagic degradation of AIM2 by inducing AIM2 ubiquitination and binding to p62 in CD4+ T cells. AIM2 attenuates AKT and FOXO1 phosphorylation, MYC signaling, and glycolysis, thereby promoting the stability of Treg cells during experimental autoimmune encephalomyelitis (EAE). Our findings suggest that TRIM11 serves as a potential target for immunotherapeutic intervention for dysregulated immune responses that lead to autoimmunity and cancers. [Display omitted] •TRIM11 specifically negatively regulates Treg cell differentiation in CD4+ T cells•TRIM11 interacts with AIM2 and induces AIM2 ubiquitination in CD4+ T cells•TRIM11 promotes the selective autophagic degradation of AIM2 dependent on p62 Yu et al. demonstrate that TRIM11 exerts a negative regulatory effect on Treg cell differentiation by facilitating the ubiquitination and selective autophagic degradation of AIM2 in a p62-dependent manner, thereby promoting the development of experimental autoimmune encephalomyelitis (EAE).