mTORC1 stimulates cell growth through SAM synthesis and m(6)A mRNA-dependent control of protein synthesis.
mTORC1 stimulates cell growth through SAM synthesis and m(6)A mRNA-dependent control of protein synthesis.
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DOI：
10.1016/j.molcel.2021.03.009
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发表时间：
2021-05-20
期刊：
影响因子：
16
通讯作者：
Ben-Sahra I
中科院分区：
文献类型：
--
作者：
Villa E;Sahu U;O'Hara BP;Ali ES;Helmin KA;Asara JM;Gao P;Singer BD;Ben-Sahra I
雷帕霉素复合物1 （mTORC1）的机制靶点调节代谢和细胞生长，以响应营养、生长和致癌信号。我们发现mTORC1通过控制蛋氨酸腺苷转移酶2 α (methionine adenosyltransferase 2 α, MAT2A)的表达，刺激主要甲基供体s -腺苷蛋氨酸（SAM）的合成。转录因子c-MYC位于mTORC1的下游，直接结合MAT2A的内含子1并促进其表达。此外，mTORC1增加了Wilms ' tumor 1- associated protein （WTAP）的蛋白丰度，WTAP是人n6 -甲基腺苷（m6A） RNA甲基转移酶复合物的正调控亚基。mTORC1信号通过控制MAT2A和WTAP水平，刺激m6A RNA修饰，促进蛋白质合成和细胞生长。抑制MAT2A后，细胞内SAM水平的下降会降低m6A RNA修饰、蛋白质合成速率和肿瘤生长。因此，mTORC1通过控制SAM和WTAP水平来调节m6A RNA修饰，为合成代谢细胞生长启动翻译机制。Villa等研究表明mTORC1激活通过控制s -腺苷蛋氨酸（SAM）合成和WTAP蛋白丰度刺激mRNA的n6 -腺苷甲基化（m6A）。mTORC1促进WTAP水平的增加，并同步增加MAT2A表达以产生SAM和m6A RNA甲基化，以支持蛋白质合成和肿瘤生长。
The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient, growth, and oncogenic signals. We found that mTORC1 stimulates the synthesis of the major methyl donor, S-adenosylmethionine (SAM), through the control of methionine adenosyltransferase 2 alpha (MAT2A) expression. The transcription factor c-MYC, downstream of mTORC1, directly binds to intron 1 of MAT2A and promotes its expression. Furthermore, mTORC1 increases the protein abundance of Wilms’ tumor 1-associating protein (WTAP), the positive regulatory subunit of the human N6-methyladenosine (m6A) RNA methyltransferase complex. Through the control of MAT2A and WTAP levels, mTORC1 signaling stimulates m6A RNA modification to promote protein synthesis and cell growth. A decline in intracellular SAM levels upon MAT2A inhibition decreases m6A RNA modification, protein synthesis rate, and tumor growth. Thus, mTORC1 adjusts m6A RNA modification through the control of SAM and WTAP levels to prime the translation machinery for anabolic cell growth. Villa et al. showed that mTORC1 activation stimulates N6-adenosine methylation of mRNA (m6A) through the control of S-adenosylmethionine (SAM) synthesis and WTAP protein abundance. mTORC1 promotes an increase in WTAP levels and concordantly increases MAT2A expression for SAM production and m6A RNA methylation to support protein synthesis and tumor growth.
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影响因子：
5.5
作者：
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影响因子：
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10.1152/ajplung.00262.2015
发表时间：
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影响因子：
4.9
作者：
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通讯作者：
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影响因子：
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作者：
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