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

Hong-Wen Tang1,2, Jui-Hsia Weng3, Wen Xing Lee4

  • 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore; hongwen.tang@duke-nus.edu.sg perrimon@receptor.med.harvard.edu.

Proceedings of the National Academy of Sciences of the United States of America
|March 2, 2021
PubMed

Insights

Mechanistic Target of Rapamycin Complex 1 (mTORC1) regulates cell growth. It controls the m6A methyltransferase complex (MTC) via the CCT complex to suppress autophagy by degrading autophagy-related mRNAs.

Area of Science:

  • Molecular Biology
  • Cellular Metabolism
  • RNA Biology

Background:

  • Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a key regulator of cell growth, metabolism, and cellular responses to environmental cues.
  • mTORC1 plays critical roles in RNA biogenesis and processing, indicating its involvement in post-transcriptional gene regulation.
  • Autophagy is a fundamental cellular process for degrading and recycling damaged components, tightly regulated by various signaling pathways.

Purpose of the Study:

  • To investigate the role of mTORC1 in regulating RNA methylation during autophagy.
  • To identify downstream effectors of mTORC1 involved in RNA processing and autophagy suppression.
  • To elucidate the molecular mechanism linking mTORC1 signaling to m6A RNA methylation and autophagy.

Main Methods:

  • Utilized Drosophila and human cell culture models to study mTORC1 signaling and autophagy.
  • Investigated the interaction between mTORC1, the m6A methyltransferase complex (MTC), and the Chaperonin Containing Tailless complex polypeptide 1 (CCT) complex.
  • Analyzed m6A RNA methylation levels on autophagy-related genes using molecular biology techniques.

Main Results:

  • Identified the m6A methyltransferase complex (MTC) as a downstream effector of mTORC1 during autophagy.
  • Demonstrated that the CCT complex acts as a crucial link, mediating mTORC1's activation of MTC.
  • Showed that mTORC1-activated CCT stabilizes MTC, leading to increased m6A methylation of autophagy-related mRNAs, promoting their degradation and suppressing autophagy.

Conclusions:

  • Revealed an evolutionarily conserved mechanism where mTORC1 signaling converges with m6A RNA methylation to suppress autophagy.
  • Established a novel regulatory axis involving mTORC1, CCT, and MTC in controlling autophagy through mRNA degradation.
  • Highlighted the significance of m6A RNA methylation in the intricate regulation of cellular metabolic and growth processes.
Keywords:
autophagychaperonin containing Tailless complex polypeptide 1 (CCT)m6A RNA methylationm6A methyltransferase complex (MTC)mTORC1

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