BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1 alpha

Rodriguez D.A.; Zamorano S.; Lisbona, F; Rojas-Rivera, D; Urra, H; Cubillos-Ruiz J.R.; Armisen, R; Henriquez D.R.; H Cheng E.; Letek M.; Vaisar T.; Irrazabal T.; Gonzalez-Billault, C; Letai A.; Pimentel-Muieos F.X.; et. al.

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.

Más información

Título según WOS: BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1 alpha
Título según SCOPUS: BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1?
Título de la Revista: EMBO JOURNAL
Volumen: 31
Número: 10
Editorial: WILEY-BLACKWELL
Fecha de publicación: 2012
Página de inicio: 2322
Página final: 2335
Idioma: English
URL: http://www.scopus.com/inward/record.url?eid=2-s2.0-84861188701&partnerID=40&md5=6f195dc9ff5a2c6dee1572ff47821268
DOI:

10.1038/emboj.2012.84

Notas: ISI, SCOPUS