Artículos de revistas
BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α
Fecha
2012Registro en:
EMBO Journal, Volumen 31, Issue 10, 2018, Pages 2322-2335
02614189
14602075
10.1038/emboj.2012.84
Autor
Rodriguez, Diego A.
Zamorano, Sebastian
Lisbona, Fernanda
Rojas Rivera, Diego
Urra, Hery
Cubillos-Ruiz, Juan R.
Armisen Yáñez, Ricardo
Henriquez, Daniel R.
Cheng, Emily
Letek, Michal
Vaisar, Tomas
Irrazabal, Thergiory
González Billault, Christian
Letai, Antho
Institución
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-