USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis

The functional integrity of Treg cells is interwoven with cellular metabolism; however, the mechanisms governing Treg cell metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited RNA m6A reader YTHDF1-mediated c-Myc translation to maintain Treg cell metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg cell signature in colorectal cancer and gastric cancer patient samples. USP47 ablation compromised Treg cell homeostasis and function in vivo, resulting in the development of inflammatory disorders, and boosted antitumor immune responses. USP47 deficiency in Treg cells triggered the accumulation of the c-Myc protein and in turn exacerbated hyperglycolysis. Mechanistically, USP47 prevented YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency. Our findings reveal that USP47 directs m6A-dependent metabolic programs to orchestrate Treg cell homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting USP47.