Basic—Liver, Pancreas, and Biliary TractCathepsin L Inactivates Human Trypsinogen, Whereas Cathepsin L-Deletion Reduces the Severity of Pancreatitis in Mice
Section snippets
Materials and Methods
Please refer to Supplementary Materials and Methods for more detailed descriptions.
Subcellular Localization and Sorting of CTSL Into the Secretory Pathway
A prerequisite for a biologic relevance of CTSL in pancreatitis would be its expression in the exocrine pancreas and its colocalization with trypsinogen. All of these have previously been established for CTSB5, 8 and could also be operative for CTSL because of great similarities between the 2 lysosomal proteases. Blotting CTSL in the pancreatic juice of mice and humans resulted in a strong signal for pro-CTSL (31 kilodaltons), single chain CTSL, as well as heavy chain CTSL (Figure 1A).
Discussion
The underlying mechanism of acute pancreatitis has long been thought to involve autodigestion of the pancreas by its own digestive proteases. Under physiologic conditions, the pancreas is protected by a variety of mechanisms that include storage and processing of digestive enzymes in membrane-confined vesicles, transport of proteases to the lumen as inactive precursor zymogens, presence of protease inhibitors, and absence of the physiologic activator enterokinase from the pancreas. Several
Acknowledgments
The authors thank Dr B. Schmidt, Zentrum für Biochemie und Molekulare Zellbiologie, Göttingen, for sequencing assistance and V. Krause, C. Jechorek, K. Mülling, and N. Loth for technical assistance and D. Schwenn for writing assistance.
T.W. and J.M. contributed equally as first authors.
W.H. and M.M.L. contributed equally as senior authors.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by grants from the Deutsche ForschungsgemeinschaftDFG HA2080/7-1, LE 625/8-1, LE 625/9-1, MA4115/1-2, DFG GRK 840 E3 and E4; Mildred Scheel Stiftung10-2031-Le I and 10-6977-Re, BMBF-NBL3 01 ZZ 0403; and Alfried-Krupp Foundation (Graduiertenkolleg Tumorbiologie) and NIHDK058088 to MST.