The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells.

Ropolo, Alejandro; Grasso, Daniel; Pardo, Romina; Sacchetti, Maria L; Archange, Cendrine; Lo Re, Andrea; Seux, Mylene; Nowak, Jonathan; Gonzalez, Claudio D; Iovanna, Juan L; Vaccaro, Maria I

Ropolo, Alejandro; Grasso, Daniel; Pardo, Romina; Sacchetti, Maria L; Archange, Cendrine; Lo Re, Andrea; Seux, Mylene; Nowak, Jonathan; Gonzalez, Claudio D; Iovanna, Juan L; Vaccaro, Maria I.

Afiliação

Ropolo A; Department of Physiology, School of Medicine, University of Buenos Aires, and CEMIC University Hospital, 4102 Av. E. Galvan, Buenos Aires C1431FWO, Argentina.

J Biol Chem ; 282(51): 37124-33, 2007 Dec 21.

Article em En | MEDLINE | ID: mdl-17940279

RESUMO

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.

Assuntos

Autofagia; Proteínas de Membrana/biossíntese; Pancreatite Necrosante Aguda/metabolismo; Fagossomos/metabolismo; Adenina/análogos & derivados; Adenina/farmacologia; Animais; Antibióticos Antineoplásicos/farmacologia; Proteínas Reguladoras de Apoptose/genética; Proteínas Reguladoras de Apoptose/metabolismo; Autofagia/efeitos dos fármacos; Autofagia/genética; Proteína Beclina-1; Células HeLa; Humanos; Proteínas de Membrana/genética; Proteínas de Membrana/metabolismo; Camundongos; Proteínas Associadas aos Microtúbulos/genética; Proteínas Associadas aos Microtúbulos/metabolismo; Células NIH 3T3; Neoplasias/genética; Neoplasias/metabolismo; Neoplasias/patologia; Doenças Neurodegenerativas/genética; Doenças Neurodegenerativas/metabolismo; Doenças Neurodegenerativas/patologia; Pancreatite Necrosante Aguda/genética; Pancreatite Necrosante Aguda/patologia; Fagossomos/genética; Fagossomos/ultraestrutura; Ligação Proteica/efeitos dos fármacos; Ligação Proteica/genética; Proteínas/genética; Proteínas/metabolismo; RNA Interferente Pequeno/farmacologia; Sirolimo/farmacologia

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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Fagossomos / Pancreatite Necrosante Aguda / Proteínas de Membrana Tipo de estudo: Prognostic_studies Idioma: En Revista: J Biol Chem Ano de publicação: 2007 Tipo de documento: Article País de afiliação: Argentina País de publicação: Estados Unidos

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