Pancreatitis has been suspected for a long time to have an autodigestive genesis. The main events occurring in the pancreatic acinar cell that initiate acute pancreatitis include inhibition of zymogen secretion and intracellular activation of proteases. Chymotrypsin C (CTRC) is a protective protease that limits trypsin and trypsinogen proteolytic activity. Hereditary pancreatitis-associated CTRC mutants such as p.A73T and p.G61R precipitate within the endoplasmic reticulum (ER) causing ER stress. We found that expression of these mutants reduces amylase secretion from carbachol-stimulated rat pancreatic acinar cells AR42J and isolated mice pancreatic acini. Furthermore, this expression also reduces the levels of acetylated tubulin by increasing both the levels and phosphorylation of the deacetylase SIRT2. Remarkably, inhibition of SIRT2 not only greatly recovers tubulin acetylation, but also amylase secretion in pancreatic acinar cells and isolated acini. However, SIRT2 inhibition does not rescue secretion of the CTRC mutants. These results strongly suggest that CTRC variants associated to ER stress inhibit secretagogue-stimulated pancreatic zymogen secretion by altering microtubule stability. Of note, the extent of this inhibition correlates with the degree of ER stress exhibited by the particular CTRC variant. (C) 2015 Elsevier Inc. All rights reserved.