Secretory Autophagy via VMP1-Containing Extracellular Vesicles in Pancreatic Stress Responses
Tadic, M. S.; Renna, F. J.; Lopez, M. H.; Mingorance, F. L.; Orquera, T.; Chiappetta, D.; Ropolo, A. J.; Vaccaro, M. I.
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Cellular stress activates mechanisms such as autophagy and vesicular trafficking to maintain homeostasis in pathological conditions like acute pancreatitis. Vacuole Membrane Protein 1 (VMP1), an autophagy-related protein implicated in pancreatitis, diabetes, and pancreatic cancer, triggers autophagy through ubiquitination and interaction with BECN1. Here, we show that VMP1 is secreted into the extracellular medium and incorporated into extracellular vesicle (EV) membranes. Using cells expressing VMP1-tagged plasmids, we isolated VMP1- containing EVs (VMP1-EVs) by ultracentrifugation and immunoisolation. VMP1-EV secretion decreased with mTOR inhibition and in Atg5-deficient cells. In pancreatic acinar cells, endogenous VMP1 secretion increased under stress, including blocked autophagic flux and experimental pancreatitis. In a rat pancreatitis model, VMP1 secretion in pancreatic juice was also elevated. TEM and DLS analyses revealed VMP1-EVs of [~]150 nm. LC3-II was detected in VMP1-EVs, and its release increased under lysosomal blockade. VMP1 downregulation reduced LC3 and p62 secretion, demonstrating that VMP1 drives a secretory autophagy pathway relevant to pancreatic pathophysiology.
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