title: BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha.
abstract: Adaptation to endoplasmic reticulum (ER) stress depends on the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Bax inhibitor-1 (BI-1) is an evolutionarily conserved ER-resident protein that suppresses cell death. Here we have investigated the role of BI-1 in the UPR. BI-1 expression suppressed IRE1alpha activity in fly and mouse models of ER stress. BI-1-deficient cells displayed hyperactivation of the ER stress sensor IRE1alpha, leading to increased levels of its downstream target X-box-binding protein-1 (XBP-1) and upregulation of UPR target genes. This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1alpha, decreasing its ribonuclease activity. Finally, BI-1 deficiency increased the secretory activity of primary B cells, a phenomenon regulated by XBP-1. Our results suggest a role for BI-1 in early adaptive responses against ER stress that contrasts with its known downstream function in apoptosis.
authors.affiliation: Institute of Biomedical Sciences, FONDAP Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Lisbona
authors.forename: Diego
authors.initials: D
authors.lastname: Rojas-Rivera
authors.forename: Peter
authors.initials: P
authors.lastname: Thielen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zamorano
authors.forename: Derrick
authors.initials: D
authors.lastname: Todd
authors.forename: Fabio
authors.initials: F
authors.lastname: Martinon
authors.forename: Alvaro
authors.initials: A
authors.lastname: Glavic
authors.forename: Christina
authors.initials: C
authors.lastname: Kress
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lin
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz