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Title

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

AuthorsRodriguez, Diego A.; Letek, Michal; Pimentel-Muiños, Felipe X. ; Hetz, Claudio
Issue Date2012
PublisherNature Publishing Group
CitationEMBO Journal 31: 2322-2335 (2012)
AbstractAdaptation 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.
Descriptionet al.
URIhttp://hdl.handle.net/10261/59529
DOI10.1038/emboj.2012.84
Identifiersissn: 0261-4189
e-issn: 1460-2075
Appears in Collections:(IBMCC) Artículos
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