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

ALEJANDRO JAVIER ROPOLO; GRASSO, D.; PARDO, R.; SACCHETTI, M.L.; ARCHANGE, C.; LO RE, A.; SEUX, M.; NOWAK, J.; GONZALEZ, C. D.; IOVANNA, J. L.; VACCARO, M. I.

JOURNAL OF BIOLOGICAL CHEMISTRY

The American Society for Biochemistry and Molecular Biology

Lugar: Bethesda, MD, USA.; 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. VMP1 expression induces the formation of ultrastructural features of autophagy and recruitment of the microtubule-associated protein 1 light-chain 3 (LC3) that is inhibited after treatment with the autophagy inhibitor 3-methiladenine (3-MA). 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, a marker of the autophagosomes. It interacts with Beclin 1, a mammalian autophagy initiator, through 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.