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


Authors: Rodriguez, D. A.; Zamorano, S.; Lisbona, F.; Rojas-Rivera, D.; Urra, H.; Cubillos-Ruiz, J. R.; Armisen, R.; Henriquez, D. R.; Cheng, E. H.; Letek, M.; Vaisar, T.; Irrazabal, T.; Gonzalez-Billault, C.; Letai, A.; Pimentel-Muiéos, F. X.; Kroemer, G.; Hetz, C.
Article Title: BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α
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 IRE1αinteractor. Immun oprecipitation experiments confirmed this interaction and further detected the association of IRE1αwith 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 IRE1αRNAse 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. © 2012 European Molecular Biology Organization.
Keywords: er stress; bh3-only proteins; bim; ire1a modulation; puma
Journal Title: EMBO Journal
Volume: 31
Issue: 10
ISSN: 0261-4189
Publisher: Wiley Blackwell  
Date Published: 2012-04-17
Start Page: 2322
End Page: 2335
Language: English
DOI: 10.1038/emboj.2012.84
PROVIDER: scopus
PMCID: PMC3364744
PUBMED: 22510886
DOI/URL:
Notes: --- - "Export Date: 4 June 2012" - "CODEN: EMJOD" - "Source: Scopus"
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  1. Emily H Cheng
    78 Cheng