BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α. Academic Article uri icon

Overview

abstract

  • Adaptation to endoplasmic reticulum (ER) stress depends on the activation of the unfolded protein response (UPR) stress sensor inositol-requiring enzyme 1α (IRE1α), which functions as an endoribonuclease that splices the mRNA of the transcription factor XBP-1 (X-box-binding protein-1). Through a global proteomic approach we identified the BCL-2 family member PUMA as a novel IRE1α interactor. Immun oprecipitation experiments confirmed this interaction and further detected the association of IRE1α with BIM, another BH3-only protein. BIM and PUMA double-knockout cells failed to maintain sustained XBP-1 mRNA splicing after prolonged ER stress, resulting in early inactivation. Mutation in the BH3 domain of BIM abrogated the physical interaction with IRE1α, inhibiting its effects on XBP-1 mRNA splicing. Unexpectedly, this regulation required BCL-2 and was antagonized by BAD or the BH3 domain mimetic ABT-737. The modulation of IRE1α RNAse activity by BH3-only proteins was recapitulated in a cell-free system suggesting a direct regulation. Moreover, BH3-only proteins controlled XBP-1 mRNA splicing in vivo and affected the ER stress-regulated secretion of antibodies by primary B cells. We conclude that a subset of BCL-2 family members participates in a new UPR-regulatory network, thus assuming apoptosis-unrelated functions.

publication date

  • April 17, 2012

Research

keywords

  • Apoptosis Regulatory Proteins
  • Endoribonucleases
  • Membrane Proteins
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Signal Transduction
  • Tumor Suppressor Proteins
  • Unfolded Protein Response

Identity

PubMed Central ID

  • PMC3364744

Scopus Document Identifier

  • 84861188701

Digital Object Identifier (DOI)

  • 10.1038/emboj.2012.84

PubMed ID

  • 22510886

Additional Document Info

volume

  • 31

issue

  • 10