mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1-JNK pathway

Cell Death Differ. 2012 Feb;19(2):310-20. doi: 10.1038/cdd.2011.98. Epub 2011 Jul 22.

Abstract

Mammalian target of rapamycin (mTOR) has a key role in the regulation of an array of cellular function. We found that rapamycin, an inhibitor of mTOR complex 1 (mTORC1), attenuated endoplasmic reticulum (ER) stress-induced apoptosis. Among three major branches of the unfolded protein response, rapamycin selectively suppressed the IRE1-JNK signaling without affecting PERK and ATF6 pathways. ER stress rapidly induced activation of mTORC1, which was responsible for induction of the IRE1-JNK pathway and apoptosis. Activation of mTORC1 reduced Akt phosphorylation, which was an event upstream of IRE-JNK signaling and consequent apoptosis. In vivo, administration with rapamycin significantly suppressed renal tubular injury and apoptosis in tunicamycin-treated mice. It was associated with enhanced phosphorylation of Akt and suppression of JNK activity in the kidney. These results disclosed that, under ER stress conditions, mTORC1 causes apoptosis through suppression of Akt and consequent induction of the IRE1-JNK pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • Endoplasmic Reticulum Stress*
  • Enzyme Activation
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Kidney / enzymology
  • Kidney / injuries
  • Kidney / pathology
  • MAP Kinase Signaling System*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism*
  • mTOR Associated Protein, LST8 Homolog

Substances

  • Membrane Proteins
  • Transcription Factors
  • mLST8 protein, rat
  • mTOR Associated Protein, LST8 Homolog
  • Ern2 protein, rat
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases