Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival

PLoS One. 2013 Oct 18;8(10):e76941. doi: 10.1371/journal.pone.0076941. eCollection 2013.

Abstract

The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • CHO Cells
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Cell Survival
  • Cricetinae
  • Cricetulus
  • Endoplasmic Reticulum / metabolism*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • Intracellular Membranes / metabolism
  • Mice
  • Microscopy, Confocal
  • Mitochondria / metabolism*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Receptors, sigma / genetics
  • Receptors, sigma / metabolism*
  • Signal Transduction*

Substances

  • Molecular Chaperones
  • Reactive Oxygen Species
  • Receptors, sigma
  • sigma-1 receptor
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases