title: The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells.
abstract: Autophagy is a degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells, and it is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes. Autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. We have previously characterized the vacuole membrane protein 1 (VMP1) gene, which is highly activated in acute pancreatitis, a disease associated with morphological changes resembling autophagy. Here we show that VMP1 expression triggers autophagy in mammalian cells. VMP1 expression induces the formation of ultrastructural features of autophagy and recruitment of the microtubule-associated protein 1 light-chain 3 (LC3), which is inhibited after treatment with the autophagy inhibitor 3-methiladenine. VMP1 is induced by starvation and rapamycin treatments. Its expression is necessary for autophagy, because VMP1 small interfering RNA inhibits autophagosome formation under both autophagic stimuli. VMP1 is a transmembrane protein that co-localizes with LC3, a marker of the autophagosomes. It interacts with Beclin 1, a mammalian autophagy initiator, through the VMP1-Atg domain, which is essential for autophagosome formation. VMP1 endogenous expression co-localizes with LC3 in pancreas tissue undergoing pancreatitis-induced autophagy. Finally, VMP1 stable expression targeted to pancreas acinar cell in transgenic mice induces autophagosome formation. Our results identify VMP1 as a novel autophagy-related membrane protein involved in the initial steps of the mammalian cell autophagic process.
authors.affiliation: Department of Physiology, School of Medicine, University of Buenos Aires, and CEMIC University Hospital, 4102 Av. E. Galvan, Buenos Aires C1431FWO, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ropolo
authors.forename: Daniel
authors.initials: D
authors.lastname: Grasso
authors.forename: Romina
authors.initials: R
authors.lastname: Pardo
authors.forename: Maria L
authors.initials: ML
authors.lastname: Sacchetti
authors.forename: Cendrine
authors.initials: C
authors.lastname: Archange
authors.forename: Andrea
authors.initials: A
authors.lastname: Lo Re
authors.forename: Mylene
authors.initials: M
authors.lastname: Seux
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nowak
authors.forename: Claudio D
authors.initials: CD
authors.lastname: Gonzalez
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Maria I
authors.initials: MI
authors.lastname: Vaccaro
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071186:Beclin-1; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D034741:RNA, Small Interfering; C526584:VMP1 protein, human; C025946:3-methyladenine; D000225:Adenine; D020123:Sirolimus