Rate of Autoactivation Determines Pancreatitis Phenotype in Trypsinogen Mutant Mice

Abstract

The digestive protease trypsin plays a central role in the onset and progression of pancreatitis. 1 Hegyi E. et al. Dig Dis Sci. 2017; 62: 1692-1701 Crossref PubMed Scopus (100) Google Scholar Ectopic conversion of the inactive precursor trypsinogen to active trypsin in the pancreas is an early event in disease development. Biochemically, trypsinogen is activated by limited proteolysis of its activation peptide, which can be cleaved by 3 different enzymes: enteropeptidase (enterokinase), trypsin (autoactivation), and cathepsin B (CTSB) (Figure 1A). Because enteropeptidase is not expressed in the pancreas, pathologic intrapancreatic trypsinogen activation can only occur through autoactivation or by CTSB-mediated activation. Inborn mutations of human cationic trypsinogen (encoded by the serine protease 1, PRSS1, gene) accelerate trypsinogen autoactivation and cause hereditary chronic pancreatitis (CP). 2 Mayerle J. et al. Gastroenterology. 2019; 156: 1951-1968 Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar In contrast, human genetic studies and functional analysis of trypsinogen mutants failed to substantiate a pathogenic role for CTSB-mediated trypsinogen activation in CP (references in Demcsák et al 3 Demcsák A. et al. Sci Rep. 2019; 9: 9188 Crossref PubMed Scopus (5) Google Scholar ).