m 6 A RNA modification guides alternative polyadenylation to maintain T cell quiescence

N 6 -Methyladenosine (m 6 A) is primarily enriched in the last exons and 3′ untranslated regions (3′UTRs) of messenger RNAs (mRNAs) and is associated with T cell homeostasis. Upon T cell activation, global mRNA 3′UTR shortening is facilitated through alternative polyadenylation (APA). However, it is unclear how T cells coordinate these two important posttranscriptional regulatory events to maintain quiescence. Here, we found that the m 6 A “writer” METTL3 directly interacts with APA factor NUDT21 and guided poly(A) site selection. Deletion of Nudt21 in T cells resulted in simultaneous overactivation and accelerated apoptosis, leading to T cell loss and impaired adaptive immune function. Mechanistically, METTL3 recruits NUDT21 to the proximal poly(A) site of Rragd mRNA, generating long 3′UTR with m 6 A modifications. Nudt21 deficiency causes Rragd 3′UTR shortening and increases Rragd expression, leading to overactivation of mammalian target of rapamycin signaling. Our study reveals an m 6 A-guided poly(A) site selection mechanism and defines in vivo roles of m 6 A-APA cross-talk in maintaining T cell quiescence.