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 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.
authors.affiliation: Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, Santiago, Chile.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Rodriguez
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zamorano
authors.forename: Fernanda
authors.initials: F
authors.lastname: Lisbona
authors.forename: Diego
authors.initials: D
authors.lastname: Rojas-Rivera
authors.forename: Hery
authors.initials: H
authors.lastname: Urra
authors.forename: Juan R
authors.initials: JR
authors.lastname: Cubillos-Ruiz
authors.forename: Ricardo
authors.initials: R
authors.lastname: Armisen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Henriquez
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.forename: Michal
authors.initials: M
authors.lastname: Letek
authors.forename: Tomas
authors.initials: T
authors.lastname: Vaisar
authors.forename: Thergiory
authors.initials: T
authors.lastname: Irrazabal
authors.forename: Christian
authors.initials: C
authors.lastname: Gonzalez-Billault
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.forename: Felipe X
authors.initials: FX
authors.lastname: Pimentel-Muiños
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D004722:Endoribonucleases / Q000378:metabolism*; D055786:Gene Knockout Techniques; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020543:Proteome / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D020543:Proteome; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases