CONICET | Buscador de Institutos y Recursos Humanos

Molecular mechanism underlying acute pancreatitis-induced autophagy M.I. Molejon, A. Ropolo, V. Boggio, G. Valenzuela, T. Rittaco, M.I. Vaccaro Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina We characterized the Vacuole Membrane Protein 1 -VMP1- as an essential autophagy-related transmembrane protein which expression activated autophagy during acute panceratitis. VMP1 triggers autophagosome formation even under nutrient-replete conditions and its expression acts as a switch for autophagy in pancreas diseases. In the current study, we report that VMP1 expression regulates the autophagosome formation in pancreatic cells by the interaction with the BH3 domain of Beclin 1. This event allows the recruitment of the Beclin 1-hVps34 complex to the autophagosome formation site where it mediates autophagosome formation in human cells. We found that the VMP1-Atg domain binds to the Beclin1-BH3 domain in a manner that VMP1 expression inhibits Beclin1-Bcl2 interaction; partitioning Beclin 1 to the autophagic pathway. We show that VMP1-Atg domain is required for both forming the Class III PI3K complex and inducing its activity to function in the autophagy. Moreover, we found that the novel VMP1-Beclin1-hVps34 complex favors the recruitment of ATG16L and topologically links two steps of the autophagy core molecular machinery, named the Class III PI3K and the ATG16L-LC3 lipidation systems. Finally, we show that the interplay between VMP1 and the Beclin 1-hVps34 complex is triggered by cerulein-induced pancreatitis in pancreatic cells. Collectively, these findings reveal a novel molecular mechanism that requires VMP1-Atg and Beclin1-BH3 domains and involves VMP1-Beclin1-hVps34 complex interaction, which regulates pancreatitis-induced autophagy. The association of this pathway to disease-related autophagy is of significant clinical relevance.

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