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m6A RNA modification guides alternative polyadenylation to maintain T cell quiescence

Xingli Zhang1,2,3, Haixin Li1,4, Gaoyang Wang1

  • 1Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Science Advances
|May 13, 2026
PubMed

Insights

The m6A writer METTL3 guides polyadenylation site selection via NUDT21 interaction, maintaining T cell quiescence. Disrupting this m6A-APA crosstalk leads to T cell overactivation, apoptosis, and immune dysfunction.

Area of Science:

  • Immunology
  • Molecular Biology
  • RNA Biology

Background:

  • N6-Methyladenosine (m6A) modifications and alternative polyadenylation (APA) are crucial posttranscriptional regulatory events.
  • Both m6A and APA influence messenger RNA (mRNA) 3' untranslated regions (3'UTRs) and are linked to T cell homeostasis.
  • The interplay between m6A and APA in maintaining T cell quiescence remains largely unelucidated.

Purpose of the Study:

  • To investigate the coordination between m6A modification and APA in T cells.
  • To elucidate the molecular mechanisms underlying T cell quiescence maintenance.
  • To define the in vivo roles of m6A-APA crosstalk in T cell function.

Main Methods:

  • Investigated the interaction between METTL3 (an m6A writer) and NUDT21 (an APA factor).
  • Utilized genetic deletion of Nudt21 in T cells to assess its functional consequences.
  • Analyzed mRNA 3'UTR length, m6A modification status, and gene expression, including Rragd and mTOR signaling.

Main Results:

  • METTL3 directly interacts with NUDT21, guiding poly(A) site selection.
  • T cell-specific deletion of Nudt21 caused T cell overactivation and apoptosis, impairing adaptive immunity.
  • METTL3-NUDT21 interaction at the Rragd mRNA proximal poly(A) site generates long 3'UTRs with m6A; Nudt21 deficiency shortens Rragd 3'UTR, increasing its expression and mTOR signaling.

Conclusions:

  • A novel m6A-guided poly(A) site selection mechanism is revealed.
  • m6A-APA crosstalk plays a critical role in maintaining T cell quiescence.
  • Dysregulation of this crosstalk leads to T cell dysfunction and immune impairment.

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