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J. Biol. Chem., Vol. 282, Issue 51, 37124-37133, December 21, 2007

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The Pancreatitis-induced Vacuole Membrane Protein 1 Triggers Autophagy in Mammalian Cells^*

Alejandro Ropolo¹, Daniel Grasso², Romina Pardo¹, Maria L. Sacchetti, Cendrine Archange, Andrea Lo Re³, Mylene Seux, Jonathan Nowak, Claudio D. Gonzalez^¶, Juan L. Iovanna⁴, and Maria I. Vaccaro⁵

From the Department of Physiology, School of Medicine, University of Buenos Aires, 2155 Paraguay p7, Buenos Aires C1121ABG, Argentina,^¶CEMIC University Hospital, 4102 Av. E. Galvan, Buenos Aires C1431FWO, Argentina, and INSERM Unite 624, 163 Avenue de Luminy, Case 915, Marseille 13288, France

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.

Received for publication, August 20, 2007 , and in revised form, October 4, 2007.

^* This work was supported in part by grants from the Agencia Nacional de Promoción Científica y Tecnológica, Consejo Nacional de Investigaciones Científicas y Técnicas, University of Buenos Aires, INSERM, and Ligue Contre le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Consejo Nacional de Investigaciones Científicas y Técnicas Fellows.

² A University of Buenos Aires Fellow.

³ An Agencia Nacional de Promoción Científica y Tecnológica Fellow.

⁴ To whom correspondence may be addressed: Tel.: 33-491-828-803; Fax: 33-491-266-219; E-mail: iovanna{at}marseille.inserm.fr.

⁵ To whom correspondence may be addressed: Tel.: 5411-5950-9500 (ext. 2127); Fax: 5411-4433-4539; E-mail: mvaccaro{at}fmed.uba.ar.

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