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| Título: | BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α |
Autor: | Rodriguez, Diego A.; Letek, Michal CSIC ORCID CVN; Pimentel-Muiños, Felipe X. CSIC ORCID ; Hetz, Claudio | Fecha de publicación: | 2012 | Editor: | Nature Publishing Group | Citación: | EMBO Journal 31: 2322-2335 (2012) | Resumen: | 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. | Descripción: | et al. | URI: | http://hdl.handle.net/10261/59529 | DOI: | 10.1038/emboj.2012.84 | Identificadores: | issn: 0261-4189 e-issn: 1460-2075 |
| Aparece en las colecciones: | (IBMCC) Artículos |
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