A Novel Selective Form of Autophagy Mediated by VMP1 Plays a Critical Role in the Protective Cell Response to Acute Pancreatitis

GRASSO, D; CAUSADA CALO, N; MOLEJÓN, MI; ROPOLO, A; VACCARO, MI

Congreso; Digestive Disease Week 2011; 2011

VMP1 is a transmembrane protein whose expression triggers autophagy and is essential for autophagosome formation in mammalian cells. VMP1 is induced in pancreatic acinar cells upon CCK-receptor hyperstimulation that mimics acute pancreatitis. Our aim was to study the role of VMP1-mediated autophagy in this pathological process. We developed ElaIVMP1 mice that constitutively express VMP1-EGFP in pancreatic acinar cells. After CCKReceptor hyperstimulation with cerulein, pancreases were removed. Electron microscopy and immunofluorescence assays of LC3 and trypsinogen showed autophagosomes containing zymogen granules in pancreases from Ela1-VMP1 mice. Magnetic immunoisolation of VMP1- autophagosomes followed by electron microscopy and western blot analysis confirmed VMP1-mediated autophagy of zymogen granules and revealed the participation of the ubiquitin-binding protein p62, which is a cargo recognition protein for autophagy. Using a permeant fluorescent substrate we found that autophagy selectively degrades the pancreatitis- activated zymogen granules since only cerulein- induced activated zymogen granules colocalized with VMP1 and LC3. We named this novel selective autophagy pathway as zymophagy. Dowregulation of VMP1 and inhibition of autophagic flow in cell and animal models demonstrated that zymophagy prevents intracellular trypsin activation and cell death. Finally, zymophagy also occurs in human pancreas with pancreatitis. In conclusion, we describe an original selective autophagy pathway mediated by VMP1 that degrades activated zymogen granules, which involves p62 and prevents cell death. Zymophagy is an inducible and selective autophagy pathway that plays a critical role in the protective cell response to disease.