Pancreatitis and Zymophagy, the selective autophagy of secretory granules granules

VACCARO MI

Buenos Aires

Congreso; Embo Ubiquitin Conferences; 2014

EMBO Conferences

Zymophagy, the selective autophagy of secretory granules.Maria Ines VaccaroInstitute for Biochemistry and Molecular Medicine, CONICET-UBAPancreatic enzymes, which break down food, are packed in secretory granules as precursormolecules called zymogens. In physiological conditions, those zymogens are activated only whenthey reach the gut, where they release nutrients that we need to survive. If this process fails and theenzymes are prematurely activated within the pancreatic cell, they break down the pancreas itselfcausing acute pancreatitis. This is a painful disease that ranges from a mild and autolimited processto a severe and lethal condition. We demonstrated that the pancreatic acinar cell is able to switch-ona refined mechanism mediated by the autophagy related transmembrane protein VMP1, whichcould explain the autolimited form of the disease. This is a novel selective form of autophagynamed zymophagy. This is a cellular process designed to specifically detect and degrade secretorygranules containing deleterious enzymes before they can digest the organ. In the current study, wecharacterize the molecules and mechanisms that mediate zymophagy. The autophagy-related proteinVMP1, the ubiquitin-protease USP9x, the ubiquitin ligase UBR1 and the ubiquitin-binding proteinp62 mediate zymophagy. We characterize the VMP1-USP9x interaction, which indicates that thereis a close relationship between the autophagy pathway and the ubiquitin recognition machineryrequired for selective autophagosome formation. Moreover, we study the role of galectins in therecognition of the altered secretory granules. This new selective autophagy is activated by hyperstimulationof G-coupled receptors during pancreatitis-induced vesicular transport alteration and inhuman pancreas by acute pancreatitis.