Leonardo Ramos Ferreira

m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways
Li HB1, Tong J1,2, Zhu S1, Batista PJ3, Duffy EE4,5, Zhao J1,6, Bailis W1, Cao G1,2, Kroehling L1, Chen Y1,7, Wang G1, Broughton JP3, Chen YG3, Kluger Y6, Simon MD4,5, Chang HY3, Yin Z2, Flavell RA1,8.
Nature. 2017 Aug 17;548(7667):338-342. doi: 10.1038/nature23450. Epub 2017 Aug 9.
August 17, 2017
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. The First Affiliated Hospital, Biomedical Translational Research Institute and Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China. Center for Dynamic Regulomes, Stanford University, Stanford, California 94305, USA. Department of Molecular Biophysics &Biochemistry, Yale University, New Haven, Connecticut 06511, USA. Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. Institute of Surgical Research, Daping Hospital, the Third Military Medical University, Chongqing 400038, China. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
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.
October 11, 2017
HSW 1057 at noon