Zymophagy, a novel mechanism for the inducible and selective autophagic degradation of secretory granules

VACCARO, MI; GRASSO, D; MOLEJÓN, MI; CAUSADA CALO, N; LO RE, A; BOGGIO, V; ROPOLO, A

Congreso; Experimental Biology 2011; 2011

Autophagy has recently elicited significant attention as a mechanism that either protects cells or promotes cell death. However, different autophagy pathways and cellular conditions remain to be elucidated. We report a thorough cellular and biochemical characterization of a novel selective autophagy that works as a protective cell response. This new selective VMP1- mediated autophagy is activated in pancreatic acinar cells during pancreatitis-induced vesicular transport alteration, in order to sequester and degrade potentially deleterious activated zymogen granules. We coined the term zymophagy to refer to this process. Zymophagy is mediated by VMP1, the ubiquitin-protease USP9x and the ubiquitin binding protein p62. Moreover, VMP1 interacts with USP9x, indicating that there is a close cooperation between the autophagy pathway and the ubiquitin recognition machinery that is required for selective autophagosome formation. Zymophagy is activated by CCK-R hyperstimulation in genetically engineered mice and cultured acinar cells, and by acute pancreatitis in humans. Furthermore, zymophagy has pathophysiological relevance by controlling pancreatitis-induced intracellular zymogen activation and helping to prevent cell death. Together, this data reveals a novel selective form of autophagy mediated by the VMP1-USP9x-p62 pathway, playing a critical role in the protective cell response to disease.