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

Department of Physiology, School of Medicine, University of Buenos Aires, and CEMIC University Hospital, 4102 Av. E. Galvan, Buenos Aires C1431FWO, Argentina.
Journal of Biological Chemistry (Impact Factor: 4.6). 01/2008; 282(51):37124-33. DOI: 10.1074/jbc.M706956200
Source: PubMed

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.

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Available from: Daniel Grasso, Jul 28, 2015
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    • "Interestingly, an accumulation of huge ubiquitinpositive protein aggregates containing the autophagy marker ATG8/LC3 was seen and p62 homolog [45] in Dictyostelium cells lacking Vmp1 gene showed. Moreover, the knockdown of VMP1 expression abolishes starvation and rapamycininduced autophagosome formation [40]. It also abolishes autophagy induced by hyperstimulation of Gq-coupled CCK receptor in pancreatic acinar cells [41] or by chemotherapy in pancreatic tumor cells [46]. "
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    • "However, like TP53INP1, TP53INP2 is involved in the control of tumor development by modulating autophagy (Nowak et al., 2009). TP53INP2 functions as a scaffold protein, recruits LC3 and beclin-1 to the autophagosome through interacting with transmembrane protein vacuole membrane protein 1 (VMP1) (Nowak and Iovanna, 2009; Nowak et al., 2009), which is essential for autophagy (Ropolo et al., 2007). Upon autophagy-inducing stress such as starvation, TP53INP2 translocates from the nucleus to the autophagosomes, interacts with VMP1, recruits LC3, and beclin-1, but no beclin-2, and play an important role in autophagy (Nowak and Iovanna, 2009; Nowak et al., 2009) (Figure 2). "
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    • "Further, the secretagogueinduced model is the most commonly employed and best characterized experimental model of acute pancreatitis [16]. Interestingly, early during this experimental model, CCK-R hyperstimulation activates the selective autophagic degradation of secretory granules in the pancreatic acinar cell [7] [17] "
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