BAX Inhibitor-1 Is a Negative Regulator of the ER Stress Sensor IRE1 alpha
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 IRE1α activity in fly and mouse models of ER stress. BI-1 deficient cells displayed hyperactivation of the ER stress sensor IRE1α, 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 IRE1α, 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 new role for BI-1 in early adaptive responses against ER stress which contrasts with its known downstream function in apoptosis.
Funding Agency Grant Number V. Harold and Leila Y. Mathers Charitable Foundation NIHA132412 FONDECYT 1070444 FONDAP 15010006 Millennium Nucleus P07-048-F Muscular Dystrophy Association Michael J. Fox Foundation for Parkinson's Research, National Parkinson's Disease High Q Foundation ICM P06-039 AI-15353 National Institutes of Health and the U.S. Department of Defense
Quote ItemMOLECULAR CELL, Volume: 33, Issue: 6, Pages: 679-691, 2009