BAX inhibitor-1 regulates autophagy by controlling the IRE1? branch of the unfolded protein response

Castillo, K; Rojas-Rivera, D; Lisbona, F; Caballero B.N.; Nassif, M; hetz C.; Sierralta, J; Court, F. A.; Schuck, S; Walter P.; Ibar C.; Glavic A.

Keywords: proteins, membrane, transport, mouse, survival, animals, expression, degradation, kidney, protein, cell, liver, drosophila, stress, acids, starvation, mice, gland, tumor, transduction, receptor, vesicles, targeting, signal, kinases, necrosis, drug, article, kinase, factor, bi, function, folding, cerevisiae, autophagy, controlled, animal, saccharomyces, ire1, study, 1, response, modified, priority, nonhuman, journal, 2, Cells,, Cultured, associated, Genetically, unclassified, Protein-Serine-Threonine, activated, salivary, Mus, Endoribonucleases, Phagosomes, Unfolded, Organisms,

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 ? (IRE1?). 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 IRE1? expression, possibly due to a displacement of TNF-receptor associated factor-2 (TRAF2) from IRE1?. 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. © 2011 European Molecular Biology Organization | All Rights Reserved.

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Título de la Revista: EMBO JOURNAL
Volumen: 30
Número: 21
Editorial: WILEY-BLACKWELL
Fecha de publicación: 2011
Página de inicio: 4465
Página final: 4478
URL: http://www.scopus.com/inward/record.url?eid=2-s2.0-80455173839&partnerID=q2rCbXpz