title: BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response.
abstract: 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.
authors.affiliation: Center for Molecular Studies of the Cell, Department of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Karen
authors.initials: K
authors.lastname: Castillo
authors.forename: Diego
authors.initials: D
authors.lastname: Rojas-Rivera
authors.forename: Fernanda
authors.initials: F
authors.lastname: Lisbona
authors.forename: Benjamín
authors.initials: B
authors.lastname: Caballero
authors.forename: Melissa
authors.initials: M
authors.lastname: Nassif
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Court
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schuck
authors.forename: Consuelo
authors.initials: C
authors.lastname: Ibar
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.forename: Jimena
authors.initials: J
authors.lastname: Sierralta
authors.forename: Alvaro
authors.initials: A
authors.lastname: Glavic
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004330:Drosophila / Q000235:genetics; D004722:Endoribonucleases / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D030781:Organisms, Genetically Modified; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013217:Starvation / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics* / Q000502:physiology
chemical_list: D000143:Acids; D008565:Membrane Proteins; C490015:Tmbim6 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases