MARCH2 mediates K27-Linked polyubiquitination of IL-2 receptor α to negatively regulate T cell proliferation

Interleukin 2 (IL-2) is a cytokine secreted by activated T cells that plays a central role in T cell proliferation and differentiation. In this study, we identified MARCH2, an E3 ubiquitin ligase of the MARCH family, as a negative regulator of IL-2 receptor alpha (IL-2Rα). MARCH2 interacts with IL-2Rα and catalyzes its K27-linked polyubiquitination and subsequent proteasomal degradation. Site-directed mutagenesis indicates that K267 of IL-2Rα is targeted by MARCH2 and mutation of this residue impairs MARCH2-mediated polyubiquitination and degradation of IL-2Rα. MARCH2-deficiency promotes IL-2-triggered STAT5 phosphorylation, effector gene expression, and proliferation of activated T cells. Our findings suggest that MARCH2 negatively regulates IL-2 signaling by targeting IL-2Rα for K27-linked polyubiquitination and proteasomal degradation, uncovering a post-translational mechanism that regulates T cell homeostasis.