PCAF-mediated acetylation of METTL3 impairs mRNA translation efficiency in response to oxidative stress  

作　　者：Cheng Liu Miao Yu Mengyuan Wang Siyuan Yang Yenan Fu Lei Zhang Chaoyang Zhu Hongquan Zhang 

机构地区：[1]Program for Cancer and Cell Biology,Department of Human Anatomy,Histology and Embryology,School of Basic Medical Sciences,Peking University International Cancer Institute,and State Key Laboratory of Molecular Oncology,Peking University Health Science Center,Beijing 100191,China [2]Department of General Surgery and Urological Surgery,Huaihe Hospital,Henan University,Kaifeng 100084,China [3]Department of Human Anatomy,Histology,and Embryology,Shenzhen University School of Medicine,Shenzhen 518055,China

出　　处：《Science China(Life Sciences)》2024年第10期2157-2168,共12页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China(2022YFA1104003,2021YFC2501003);the National Natural Science Foundation of China(82230094,81972616,81730071);Peking University Medicine Sailing Program for Young Scholars'Scientific&Technological Innovation(BMU2024YFJHPY004);the Fundamental Research Funds for the Central Universities。

摘　　要：METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity.METTL3 enhances RNA translation independently of its catalytic activity.However,the underlying mechanism is still elusive.Here,we report that METTL3 is both interacted with and acetylated at lysine 177 by the acetyltransferase PCAF and deacetylated by SIRT3.Neither the methyltransferase activity nor the stability of METTL3 is affected by its acetylation at K177.Importantly,acetylation of METTL3 blocks its interaction with EIF3H,a subunit of the translation initiation factor,thereby reducing mRNA translation efficiency.Interestingly,acetylation of METTL3 responds to oxidative stress.Mechanistically,oxidative stress enhances the interaction of PCAF with METTL3,increases METTL3 acetylation,and suppresses the interaction of METTL3 with EIF3H,thereby decreasing the translation efficiency of ribosomes and inhibiting cell proliferation.Altogether,we suggest a mechanism by which oxidative stress regulates RNA translation efficiency by the modulation of METTL3 acetylation mediated by PCAF.

关 键 词：METTL3 ACETYLATION PCAF m^(6)A oxidative stress TRANSLATION SIRT3 

分 类 号：Q75[生物学—分子生物学]