| First Author | Rodriguez DA | Year | 2012 |
| Journal | EMBO J | Volume | 31 |
| Issue | 10 | Pages | 2322-35 |
| PubMed ID | 22510886 | Mgi Jnum | J:184682 |
| Mgi Id | MGI:5426076 | Doi | 10.1038/emboj.2012.84 |
| Citation | Rodriguez DA, et al. (2012) BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1alpha. EMBO J 31(10):2322-35 |
| abstractText | Adaptation to endoplasmic reticulum (ER) stress depends on the activation of the unfolded protein response (UPR) stress sensor inositol-requiring enzyme 1alpha (IRE1alpha), 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 IRE1alpha interactor. Immun oprecipitation experiments confirmed this interaction and further detected the association of IRE1alpha 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 IRE1alpha, 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 IRE1alpha 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. |
