Zymophagy, the selective autophagy of secretory granules

VACCARO MI

Barga

Congreso; Gordon Research Conferences: Autophagy in Stress, Development & Disease; 2014

Gordon Research Conferences

Pancreatic enzymes, which break down food, are packed in secretory granules as precursor molecules called zymogens. In physiological conditions, those zymogens are activated only when they reach the gut, where they release nutrients that we need to survive. If this process fails and the enzymes are prematurely activated within the pancreatic cell, they break down the pancreas itself causing acute pancreatitis. This is a painful disease that ranges from a mild and autolimited process to a severe and lethal condition. We demonstrated that the pancreatic acinar cell is able to switch-on a refined mechanism mediated by the autophagy related transmembrane protein VMP1, which could explain the autolimited form of the disease. This is a novel selective form of autophagy named zymophagy. This is a cellular process designed to specifically detect and degrade secretory granules containing deleterious enzymes before they can digest the organ. In the current study, we characterize the molecules and mechanisms that mediate zymophagy. The autophagy-related protein VMP1, the ubiquitin-protease USP9x, the ubiquitin ligase UBR1 and the ubiquitin-binding protein p62 mediate zymophagy. We characterize the VMP1-USP9x interaction, which indicates that there is a close relationship between the autophagy pathway and the ubiquitin recognition machinery required for selective autophagosome formation. Moreover, we study the role of galectins in the recognition of the altered secretory granules. This new selective autophagy is activated by hyper-stimulation of G-coupled receptors during pancreatitis-induced vesicular transport alteration and in human pancreas by acute pancreatitis.