Intracellular autoactivation of human cationic trypsinogen mutants causes reduced trypsinogen secretion and acinar cell death.

ABSTRACT: Mutations in the activation peptide of human cationic trypsinogen have been found in patients with chronic pancreatitis. Previous biochemical studies demonstrated that mutations p.D19A, p.D22G, and p.K23R strongly stimulate trypsinogen autoactivation. In the present study, we characterized the cell biological effects of these mutants using human embryonic kidney 293T and AR42J rat acinar cells. We found that relative to wild-type trypsinogen, secretion of the mutants from transfected cells was markedly decreased. This apparent secretion defect was completely rescued by inhibition of autoactivation via (1) inclusion of the small molecule trypsin inhibitor benzamidine in the growth medium; or (2) cotransfection with the physiological trypsin inhibitor SPINK1; or (3) by mutation of the cataly

SUBMITTER: Kereszturi E 

PROVIDER: S-EPMC2785183 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature