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

H Kato1, S Nakajima, Y Saito

  • 1Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.

Cell Death and Differentiation
|July 23, 2011
PubMed

Insights

Rapamycin, an inhibitor of mTOR complex 1 (mTORC1), reduces cell death caused by endoplasmic reticulum (ER) stress. This occurs by blocking the IRE1-JNK pathway, protecting cells from ER stress-induced apoptosis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mammalian target of rapamycin (mTOR) regulates critical cellular functions.
  • Endoplasmic reticulum (ER) stress triggers apoptosis through the unfolded protein response (UPR).

Purpose of the Study:

  • To investigate the role of mTOR complex 1 (mTORC1) in ER stress-induced apoptosis.
  • To determine the specific UPR pathways affected by mTORC1 inhibition.

Main Methods:

  • Utilized rapamycin, an mTORC1 inhibitor, to study its effects on ER stress.
  • Examined the impact on IRE1-JNK, PERK, and ATF6 pathways.
  • Assessed Akt phosphorylation and JNK activity in vitro and in vivo models.

Main Results:

  • Rapamycin selectively suppressed the IRE1-JNK pathway, not PERK or ATF6.
  • ER stress induced mTORC1 activation, leading to IRE1-JNK activation and apoptosis.
  • mTORC1 activation reduced Akt phosphorylation, preceding IRE1-JNK signaling and apoptosis.
  • In vivo, rapamycin reduced renal tubular injury and apoptosis in mice.

Conclusions:

  • mTORC1 activation under ER stress promotes apoptosis via Akt suppression and IRE1-JNK pathway induction.
  • Targeting mTORC1 may offer a therapeutic strategy for conditions involving ER stress-induced apoptosis.

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