1. BH3‐only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α
- Author
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Diego A Rodriguez, Sebastian Zamorano, Fernanda Lisbona, Diego Rojas‐Rivera, Hery Urra, Juan R Cubillos‐Ruiz, Ricardo Armisen, Daniel R Henriquez, Emily H Cheng, Michal Letek, Tomas Vaisar, Thergiory Irrazabal, Christian Gonzalez‐Billault, Anthony Letai, Felipe X Pimentel‐Muiños, Guido Kroemer, and Claudio Hetz
- Subjects
Bcl-2-Like Protein 11 ,Proteome ,General Immunology and Microbiology ,Tumor Suppressor Proteins ,General Neuroscience ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Membrane Proteins ,Protein Serine-Threonine Kinases ,Corrigenda ,General Biochemistry, Genetics and Molecular Biology ,Gene Knockout Techniques ,Mice ,Proto-Oncogene Proteins ,Endoribonucleases ,Protein Interaction Mapping ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Unfolded Protein Response ,Animals ,Immunoprecipitation ,Apoptosis Regulatory Proteins ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,Protein Binding ,Signal Transduction - 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.
- Published
- 2021
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