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

ALEJANDRO ROPOLO; DANIEL GRASSO; ROMINA PARDO; CENDRINE ARCHANGE; ANDREA LO RÉ; MYLENE SEUX; JONATHAN NOWAK; CLAUDIO D GONZALEZ; JUAN IOVANNA; MARÍA INÉS VACCARO

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda; Año: 2007 vol. 282 p. 37124 - 37133

0021-9258

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. We demonstrated that VMP1 expression induces the formation of autophagosomes using electron microscopy, LC3 recruitment and PI3K inhibition. VMP1 is induced by starvation and rapamycin treatments. Its expression is necessary for autophagy since siRNA-VMP1 inhibits autophagosome formation under both autophagic stimuli. VMP1 is a trans-membrane protein that co-localizes with LC3 in vacuole membranes. It interacts with Beclin 1 through its carboxi-terminal region, which is essential for the autophagosome formation. In animal models, VMP1 endogenous expression is found in LC3 positive vacuole membranes in pancreas tissue undergoing pancreatitis-induced autophagy. Moreover, VMP1 stable expression targeted to pancreas acinar cell in transgenic mice induces the formation of LC3 positive vacuole membrane formation where VMP1 localizes. Our results identify VMP1 as a novel autophagy related membrane protein involved in the initial steps of the mammalian cell autophagic process.