m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways

Abstract

N6 -methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by ‘writers’, ‘erasers’ and ‘readers’ of this mark 1,2. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates 3,4. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that deletion of m6A ‘writer’ protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopenic mouse adoptive transfer model, naive Mettl3 deficient T cells failed to undergo homeostatic expansion and remarkably remained in the naïve state up through 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding STAT- signaling inhibitory proteins, Socs1, Socs3 and Cish, were marked by m6A, exhibited slower mRNA decay and increased mRNAs and protein expression levels in Mettl3 deficient naïve 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 plays important roles for inducible degradation of Socs mRNAs in response to IL-7 signaling in order to reprogram Naïve T cells for proliferation and differentiation. Our study elucidates for the first time 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.

RNA m6A modification and its function in diseases

“…We found that 484 RNA m 6 METTL3 depletion resulted in disrupted naïve T cell homeostasis [61]. Specifically, overexpression of SOCS family proteins prevented the activation of IL-7-STAT5 signaling, which was critical for naïve T cell homeostasis, due to the increased half-lives of m 6 A-containing mRNAs of SOCS family genes [61]. Similarly, Socs mRNA levels were also elevated in METTL3 depleting Tregs [62].…”

“…A-containing mRNAs had reduced half-lives, compared with mRNAs lacking m 6 A in ES cell [9,13]. In addition, by conditional deletion of METTL3 in T cells [61,62], we could investigate the in vivo physiological functions of m 6 A in adult mammalian cells. We found that 484 RNA m 6 METTL3 depletion resulted in disrupted naïve T cell homeostasis [61].…”

“…In addition, by conditional deletion of METTL3 in T cells [61,62], we could investigate the in vivo physiological functions of m 6 A in adult mammalian cells. We found that 484 RNA m 6 METTL3 depletion resulted in disrupted naïve T cell homeostasis [61]. Specifically, overexpression of SOCS family proteins prevented the activation of IL-7-STAT5 signaling, which was critical for naïve T cell homeostasis, due to the increased half-lives of m 6 A-containing mRNAs of SOCS family genes [61].…”

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

“…Indeed, m6A is one of the major modifications of RNA that regulates the processing, translation and decay of RNA, which plays a key role in RNA metabolism and function . Furthermore, m6A, which is mainly catalysed by METTL3, regulates RNA stability mainly through m6A‐specific binding proteins which in turn determines cellular fate and function . In particular, N 6 ‐methyladenosine (m 6 A) has been shown recently to play essential roles in various bioprocesses .…”

Post‐transcriptional control of immune responses and its potential application

“…m 6 A‐modified mRNA is recognised by a set of m 6 A‐binding ‘reader’ proteins including YTH domain‐containing proteins (YTHDF1‐3, YTHDC1‐2). It is reported that this modification plays a critical role in the mRNA degradation of immune‐related transcripts . For example, m 6 A methylation promotes the destabilisation of Socs1 , Socs3 and Cish mRNA in CD4 T cells, which are negative regulators of STAT signalling.…”