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

Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2021945118. doi: 10.1073/pnas.2021945118.

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.

Keywords: autophagy; chaperonin containing Tailless complex polypeptide 1 (CCT); m6A RNA methylation; m6A methyltransferase complex (MTC); mTORC1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autophagy*
  • Cell Line
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Orphan Nuclear Receptors
  • RNA Stability
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction*

Substances

  • Drosophila Proteins
  • NR2E1 protein, human
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • TLL protein, Drosophila
  • 6-methyladenine mRNA methyltransferase
  • Methyltransferases
  • Mechanistic Target of Rapamycin Complex 1