SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function.
SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function.
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m(6)A-RNA 甲基转移酶 METTL3 的 SUMO 化调节其功能
DOI：
10.1093/nar/gky156
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发表时间：
2018-06-01
影响因子：
14.9
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Du Y;Hou G;Zhang H;Dou J;He J;Guo Y;Li L;Chen R;Wang Y;Deng R;Huang J;Jiang B;Xu M;Cheng J;Chen GQ;Zhao X;Yu J
甲基转移酶样蛋白3（methyltransferase like 3，简称MTL 3）是哺乳动物中N6-腺苷-甲基转移酶复合物的一个重要组成部分，负责多种RNA（包括mRNA、tRNA、rRNA、小核RNA、microRNA前体和长链非编码RNA）中N6-甲基腺苷（m6 A）的修饰。然而，对胃L3的激活和翻译后修饰（PTM）的特点了解甚少。在此，我们发现SUMO 1主要在赖氨酸残基K177、K211、K212和K215处修饰胃L3，这些残基可以被SUMO 1特异性蛋白酶SENP 1还原。SUMO化的胃L3不改变其稳定性，定位和与胃L14和WTAP的相互作用，但显著抑制其m6 A甲基转移酶活性，导致mRNA中m6 A水平降低。与此一致，在内源性胃L3被敲低的人非小细胞肺癌（NSCLC）细胞系H1299-shL 3中，与野生型胃L3相比，突变型胃L3 -4KR的再表达增加了m6 A在mRNA中的丰度。通过SUMO化介导的mRNA中m6 A的改变和随后基因表达谱的改变可能直接影响H1299细胞软琼脂集落形成和异种移植瘤的生长。我们的研究结果揭示了一个重要的机制，SUMO化的胃L3调节其m6 A RNA甲基转移酶活性。
The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K177, K211, K212 and K215, which can be reduced by an SUMO1-specific protease SENP1. SUMOylation of METTL3 does not alter its stability, localization and interaction with METTL14 and WTAP, but significantly represses its m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs. Consistently with this, the abundance of m6A in mRNAs is increased with re-expression of the mutant METTL3-4KR compared to that of wild-type METTL3 in human non-small cell lung carcinoma (NSCLC) cell line H1299-shMETTL3, in which endogenous METTL3 was knockdown. The alternation of m6A in mRNAs and subsequently change of gene expression profiles, which are mediated by SUMOylation of METTL3, may directly influence the soft-agar colony formation and xenografted tumor growth of H1299 cells. Our results uncover an important mechanism for SUMOylation of METTL3 regulating its m6A RNA methyltransferase activity.
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影响因子：
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