BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response

• Published in: The EMBO journal Vol. 30; no. 21; pp. 4465 - 4478
• Main Authors: Castillo, Karen, Rojas-Rivera, Diego, Lisbona, Fernanda, Caballero, Benjamín, Nassif, Melissa, Court, Felipe A, Schuck, Sebastian, Ibar, Consuelo, Walter, Peter, Sierralta, Jimena, Glavic, Alvaro, Hetz, Claudio
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 02.11.2011; Nature Publishing Group UK; Nature Publishing Group
• Subjects: Acids - metabolism; Animals; autophagy; Autophagy - genetics; bax inhibitor-1(B1-1); Cell Survival - genetics; Cells, Cultured; Drosophila - genetics; EMBO07; EMBO37; Endoribonucleases - metabolism; Endoribonucleases - physiology; inositol requiring kinase 1 α (IRE1α); jun-terminal kinase (JNK); Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; microtubule-associated protein 1 light chain 3 (LC3); Organisms, Genetically Modified; Phagosomes - genetics; Phagosomes - metabolism; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Saccharomyces cerevisiae - genetics; Signal Transduction - genetics; Signal Transduction - physiology; Starvation - metabolism; Transport Vesicles - metabolism; Unfolded Protein Response - genetics; Unfolded Protein Response - physiology; autophagy; jun‐terminal kinase (JNK); bax inhibitor‐1(B1‐1); microtubule‐associated protein 1 light chain 3 (LC3); inositol requiring kinase 1 α (IRE1α)
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1038/emboj.2011.318

Both autophagy and apoptosis are tightly regulated processes playing a central role in tissue homeostasis. Bax inhibitor 1 (BI‐1) is a highly conserved protein with a dual role in apoptosis and endoplasmic reticulum (ER) stress signalling through the regulation of the ER stress sensor inositol requiring kinase 1 α (IRE1α). Here, we describe a novel function of BI‐1 in the modulation of autophagy. BI‐1‐deficient cells presented a faster and stronger induction of autophagy, increasing LC3 flux and autophagosome formation. These effects were associated with enhanced cell survival under nutrient deprivation. Repression of autophagy by BI‐1 was dependent on cJun‐N terminal kinase (JNK) and IRE1α expression, possibly due to a displacement of TNF‐receptor associated factor‐2 (TRAF2) from IRE1α. Targeting BI‐1 expression in flies altered autophagy fluxes and salivary gland degradation. BI‐1 deficiency increased flies survival under fasting conditions. Increased expression of autophagy indicators was observed in the liver and kidney of bi‐1 ‐deficient mice. In summary, we identify a novel function of BI‐1 in multicellular organisms, and suggest a critical role of BI‐1 as a stress integrator that modulates autophagy levels and other interconnected homeostatic processes. Bax inhibitor‐1 (BI‐1) negatively regulates the ER stress sensor IRE1α and promotes cell survival. BI‐1 attenuates starvation‐induced autophagy, presumably by displacing TRAF2 from IRE1α and interfering with JNK activation.