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Nature:暨南大学尹芝南教授发表细胞免疫研究论文

摘要 : 2017年8月9日,国际学术权威刊物自然出版集团旗下《Nature》杂志在线发表了暨南大学生物医学转化研究院/附属第一医院尹芝南教授与耶鲁大学免疫系Richard A. Flavell院士研究组合作的一篇研究论文,论文题为“m6A mRNA methylation controls T cell homeostasis by targetingIL-7/STAT5/SOCS pathway”研究论文。

2017年8月9日,国际学术权威刊物自然出版集团旗下《Nature》杂志在线发表了暨南大学生物医学转化研究院/附属第一医院尹芝南教授与耶鲁大学免疫系Richard A. Flavell院士研究组合作的一篇研究论文,论文题为“m6A mRNA methylation controls T cell homeostasis by targetingIL-7/STAT5/SOCS pathway”研究论文。尹芝南教授和Richard A. Flavell院士为本文的共同通讯作者。

T细胞是人体免疫系统的重要组成之一,其具有多种生物学功能:一方面,T细胞可以激活固有免疫系统、B淋巴细胞以及非免疫细胞;另一方面T细胞还在抑制免疫反应方面其重要的作用。T细胞功能缺陷或数量异常将直接影响机体的免疫功能。体内T细胞的稳态受到多种机制精细调控,但RNA修饰在T细胞稳态中的作用仍不清楚。

该课题组通过构建RNA N6-腺苷甲基化(m6A)修饰酶METTL3(Methyltransferase like 3)的条件性敲除小鼠模型,系统性地研究了m6A修饰调控T细胞稳态的分子机制。研究发现,T细胞内敲除RNA m6A修饰酶后,小鼠的幼稚T(NaiveT cells)细胞数量和比例显著上升,且该细胞无法进行正常的稳态增殖和分化。进一步研究发现m6A修饰可以通过靶向白介素7(Interleukin7, IL-7)介导的细胞因子信号通路抑制分子(Suppressor of Cytokine Signaling, SOCS)信使RNA的快速降解,促进幼稚T细胞重编程(Reprogram)进而启动T细胞的增殖、分化。该研究首次发现m6A修饰在T细胞维持稳态及其分化功能中的重要作用,阐明了m6A修饰调控T细胞稳态增殖的分子机制,为进一步研究RNA表观遗传学在免疫系统中的作用提供了重要的理论依据。

我校生物医学转化研究院尹芝南教授与耶鲁大学免疫系Richard A. Flavell院士建了了长期的研究生培养模式。双方课题组一直致力于T细胞的基础生物学特性研究,在阐明T细胞发育、分化和活化执行功能过程中的关键分子机制方面,做出了突破性的研究。研究成果首次发现m6A甲基化修饰在T细胞介导的疾病中的重要生物学功能,阐明了m6A调节T细胞稳态增殖的分子机制,为进一步研究RNA表观遗传学在免疫系统中的作用提供了理论依据。

原文链接:

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

原文摘要:

N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by ‘writers’, ‘erasers’ and ‘readers’ of this mark1, 2. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates3, 4. 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, naiveMettl3-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.

来源: Nature 浏览次数:0

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