BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha

Mol Cell. 2009 Mar 27;33(6):679-91. doi: 10.1016/j.molcel.2009.02.017.

Abstract

Adaptation to endoplasmic reticulum (ER) stress depends on the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Bax inhibitor-1 (BI-1) is an evolutionarily conserved ER-resident protein that suppresses cell death. Here we have investigated the role of BI-1 in the UPR. BI-1 expression suppressed IRE1alpha activity in fly and mouse models of ER stress. BI-1-deficient cells displayed hyperactivation of the ER stress sensor IRE1alpha, leading to increased levels of its downstream target X-box-binding protein-1 (XBP-1) and upregulation of UPR target genes. This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1alpha, decreasing its ribonuclease activity. Finally, BI-1 deficiency increased the secretory activity of primary B cells, a phenomenon regulated by XBP-1. Our results suggest a role for BI-1 in early adaptive responses against ER stress that contrasts with its known downstream function in apoptosis.

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

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • B-Lymphocytes / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / metabolism
  • Endoplasmic Reticulum / physiology*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Immunoglobulin M / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Splicing
  • Regulatory Factor X Transcription Factors
  • Sequence Homology, Amino Acid
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • X-Box Binding Protein 1

Substances

  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Immunoglobulin M
  • Membrane Proteins
  • Regulatory Factor X Transcription Factors
  • TMBIM6 protein, human
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, Drosophila
  • Xbp1 protein, mouse
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases