VMP1 regulates autophagy induction through the interaction with the tumor suppressor protein Beclin 1

MOLEJON MI; ROPOLO A; BOGGIO V; VACCARO MI

Congreso; Digestive Disease Week 2013; 2013

The Vacuole Membrane Protein 1 -VMP1- is a pancreatitis-associated protein that functions as an essential autophagy-related transmembrane protein conserved from worms to mammals. Expression of VMP1 triggers autophagosome formation even under nutrient-rich conditions and its expression acts as a trigger for autophagy in pancreatic disorders. Moreover, VMP1 mediates the selective autophagy of altered zymogen granules -zymophagy- in acinar cells during acute pancreatitis as a cell protective response. In the current study, we unveil the mechanism through which VMP1 expression induces the autophagosome formation. We show that VMP1 autophagy-related function requires its 20-aminoacid C-terminus hydrophilic domain, which we named VMP1-AtgD. This function is achieved through the direct binding of the VMP1-AtgD with the BH3 motif of Beclin 1. This interaction leads to the formation of a complex with the Class III phosphatidyl-3 kinase (PI3K), a key positive regulator of autophagy, at the site where autophagosomes are generated. VMP1-Beclin 1 interaction also concomitantly promotes the dissociation of Bcl-2, an autophagy inhibitor, from Beclin 1. Moreover, we show that the VMP1-Beclin 1-PI3K complex promotes the association of other autophagic core machinery proteins, such as Atg16L1 and LC3, with the autophagosomal membranes. Collectively, these findings reveal that VMP1 expression recruits and activates the Class III PI3K complex at the site of autophagosome formation.Our findings provide further understanding of VMP1 role in the induction of autophagy. The association of this pathway to pancreatitis-related autophagy is of significant relevance to experimental therapeutics.