m⁶A RNA modification guides alternative polyadenylation to maintain T cell quiescence.

Abstract

<i>N</i>⁶-Methyladenosine (m⁶A) 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 m⁶A "writer" METTL3 directly interacts with APA factor NUDT21 and guided poly(A) site selection. Deletion of <i>Nudt21</i> 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 <i>Rragd</i> mRNA, generating long 3'UTR with m⁶A modifications. <i>Nudt21</i> deficiency causes <i>Rragd</i> 3'UTR shortening and increases <i>Rragd</i> expression, leading to overactivation of mammalian target of rapamycin signaling. Our study reveals an m⁶A-guided poly(A) site selection mechanism and defines in vivo roles of m⁶A-APA cross-talk in maintaining T cell quiescence.