m 6 A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways

Nature. 2017 Aug 17;548(7667):338-342. doi: 10.1038/nature23450. Epub 2017 Aug 9.

Abstract

N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by 'writers', 'erasers' and 'readers' of this mark. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m6A 'writer' protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m6A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Adoptive Transfer
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Colitis / prevention & control
  • DNA-Binding Proteins / deficiency
  • Disease Models, Animal
  • Female
  • Homeostasis*
  • Interleukin-7 / immunology*
  • Male
  • Methylation
  • Methyltransferases / deficiency
  • Mice
  • RNA Stability
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism*
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction*
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • DNA-Binding Proteins
  • Interleukin-7
  • RNA, Messenger
  • Rag2 protein, mouse
  • STAT5 Transcription Factor
  • Socs1 protein, mouse
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • cytokine inducible SH2-containing protein
  • N6-methyladenosine (m6A)
  • Methyltransferases
  • Mettl3 protein, mouse
  • Adenosine