BAX Inhibitor-1 Is a Negative Regulator of the ER Stress Sensor IRE1α

• DOI: 10.1016/j.molcel.2009.02.017
• Publication Date: 2009-03-27T10:42:56Z
• Authors: Fernanda Lisbona; Diego Rojas-Rivera; Peter Thielen; Sebastian Zamorano; Derrick Todd; Fabio Martinon; Alvaro Glavic; Christina Kress; Jonathan H. Lin; Peter Walter; John C. Reed; Laurie H. Glimcher; Claudio Hetz
• Keywords: 0301 basic medicine; PROTEINS; RNA Splicing; Molecular Sequence Data; Apoptosis; CELLCYCLE; Protein Serine-Threonine Kinases; Endoplasmic Reticulum; Mice; 03 medical and health sciences; Endoribonucleases; Animals; Drosophila Proteins; Humans; Amino Acid Sequence; MOLIMMUNO; Molecular Biology; Cells, Cultured; Mice, Knockout; B-Lymphocytes; 0303 health sciences; UNFOLDED PROTEIN RESPONSE; Membrane Proteins; Cell Biology; Fibroblasts; DNA-Binding Proteins; Drosophila melanogaster; Immunoglobulin M; Apoptosis Regulatory Proteins

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.