Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m(6)A Methylation.
Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m(6)A Methylation.
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DOI：
10.1016/j.molcel.2020.10.026
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发表时间：
2020-11-19
期刊：
影响因子：
16
通讯作者：
He C
中科院分区：
文献类型：
--
作者：
Sun HL;Zhu AC;Gao Y;Terajima H;Fei Q;Liu S;Zhang L;Zhang Z;Harada BT;He YY;Bissonnette MB;Hung MC;He C
N6-甲基腺苷（m6 A）是最丰富的mRNA修饰，其通过胃L3-胃L14-WTAP甲基转移酶复合物安装。尽管m6 A甲基化在mRNA动力学中的重要性最近已得到充分证明，但m6 A机制的调节仍然不清楚。通过全基因组CRISPR筛选，我们将ERK通路和USP 5确定为m6 A通路的正调节因子。我们发现ERK磷酸化位于S43/S50/S525的胃L3和位于S306/S341的WTAP，然后通过USP 5去泛素化，导致m6 A甲基转移酶复合物的稳定。缺乏胃L3/WTAP磷酸化减少了m6 A标记的多能因子的衰变，并将小鼠胚胎干细胞捕获在多能状态。同样的磷酸化也可以在ERK激活的人类癌细胞中发现，并有助于肿瘤发生。总的来说，我们的研究揭示了ERK在调节m6 A甲基化中未被认识的功能。Sun等人证明ERK通路的激活通过胃L3和WTAP的磷酸化促进m6 A甲基化。胃L3的磷酸化增加与USP 5的相互作用，从而减少泛素化以稳定m6 A甲基转移酶复合物。ERK-stomach L3/WTAP信号轴的激活促进干细胞分化和肿瘤发生。
N6-methyladenosine (m6A) is the most abundant mRNA modification, which is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of m6A methylation in mRNA dynamics has been well-documented recently, the regulation of m6A machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the m6A pathway. We find that ERK phosphorylates METTL3 at S43/S50/S525 and WTAP at S306/S341, followed by deubiquitination by USP5, resulting in stabilization of the m6A methyltransferase complex. Lack of METTL3/WTAP phosphorylation reduces decay of m6A-labeled pluripotent factors and traps mouse embryonic stem cells in the pluripotent state. The same phosphorylation can also be found in ERK-activated human cancer cells and contribute to tumorigenesis. Overall, our study reveals an unrecognized function of ERK in regulating m6A methylation. Sun et al. demonstrate that activation of the ERK pathway promotes m6A methylation by phosphorylation of METTL3 and WTAP. Phosphorylation of METTL3 increases interaction with USP5, thereby decreasing ubiquitination to stabilize the m6A methyltransferase complex. Activation of the ERK-METTL3/WTAP signaling axis promotes stem cell differentiation and tumorigenesis.
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