mTORC1-chaperonin CCT signaling regulates m6A RNA methylation to suppress autophagy

Author:

Tang Hong-Wen,Weng Jui-Hsia,Lee Wen XingORCID,Hu Yanhui,Gu Lei,Cho Sungyun,Lee GinaORCID,Binari Richard,Li Cathleen,Cheng Min En,Kim Ah-RamORCID,Xu Jun,Shen Zhangfei,Xu Chiwei,Asara John M.ORCID,Blenis JohnORCID,Perrimon Norbert

Abstract

Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a central regulator of cell growth and metabolism that senses and integrates nutritional and environmental cues with cellular responses. Recent studies have revealed critical roles of mTORC1 in RNA biogenesis and processing. Here, we find that the m6A methyltransferase complex (MTC) is a downstream effector of mTORC1 during autophagy in Drosophila and human cells. Furthermore, we show that the Chaperonin Containing Tailless complex polypeptide 1 (CCT) complex, which facilitates protein folding, acts as a link between mTORC1 and MTC. The mTORC1 activates the chaperonin CCT complex to stabilize MTC, thereby increasing m6A levels on the messenger RNAs encoding autophagy-related genes, leading to their degradation and suppression of autophagy. Altogether, our study reveals an evolutionarily conserved mechanism linking mTORC1 signaling with m6A RNA methylation and demonstrates their roles in suppressing autophagy.

Funder

HHS | National Institutes of Health

U.S. Department of Defense

Starr Foundation

Human Frontier Science Program

Ministry of Science and Technology, Taiwan

Howard Hughes Medical Institute

Duke-NUS Medical School

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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