Biochemical analyses of cystatin-C dimers and cathepsin-B reveals a trypsin-driven feedback mechanism in acute pancreatitis

Jana Marielle Modenbach, Christina Möller, Saeedeh Asgarbeik, Norman Geist, Niklas Rimkus, Mark Dörr, Hannes Wolfgramm, Leif Steil, Anne Susemihl, Leonie Graf, Ole Schmöker, Dominique Böttcher, Elke Hammer, Juliane Glaubitz, Michael Lammers, Mihaela Delcea, Uwe Völker, Ali Alexander Aghdassi, Markus M. Lerch, Frank Ulrich Weiss, Uwe T. Bornscheuer () and Matthias Sendler ()
Additional contact information
Jana Marielle Modenbach: University Medicine Greifswald
Christina Möller: University of Greifswald
Saeedeh Asgarbeik: University Medicine Greifswald
Norman Geist: University of Greifswald
Niklas Rimkus: University of Greifswald
Mark Dörr: University of Greifswald
Hannes Wolfgramm: University Medicine Greifswald
Leif Steil: University Medicine Greifswald
Anne Susemihl: University of Greifswald
Leonie Graf: University of Greifswald
Ole Schmöker: University of Greifswald
Dominique Böttcher: University of Greifswald
Elke Hammer: University Medicine Greifswald
Juliane Glaubitz: University Medicine Greifswald
Michael Lammers: University of Greifswald
Mihaela Delcea: University of Greifswald
Uwe Völker: University Medicine Greifswald
Ali Alexander Aghdassi: University Medicine Greifswald
Markus M. Lerch: University Medicine Greifswald
Frank Ulrich Weiss: University Medicine Greifswald
Uwe T. Bornscheuer: University of Greifswald
Matthias Sendler: University Medicine Greifswald

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Acute pancreatitis (AP) is characterised by self-digestion of the pancreas by its own proteases. This pathophysiological initiating event in AP occurs inside pancreatic acinar cells where intrapancreatic trypsinogen becomes prematurely activated by cathepsin B (CTSB), and induces the digestive protease cascade, while cathepsin L (CTSL) degrades trypsin and trypsinogen and therefore prevents the development of AP. These proteases are located in the secretory compartment of acinar cells together with cystatin C (CST3), an endogenous inhibitor of CTSB and CTSL. The results are based on detailed biochemical analysis, site-directed mutagenesis and molecular dynamics simulations in combination with an experimental disease model of AP using CST3 deficient mice. This identifies that CST3 is a critical regulator of CTSB and CTSL activity during AP. CST3 deficient mice show a higher intracellular CTSB activity resulting in elevated trypsinogen activation accompanied by an increased disease severity. This reveals that CST3 can be cleaved by trypsin disabling the inhibition of CTSB, but not of CTSL. Furthermore, dimerised CST3 enhances the CTSB activity by binding to an allosteric pocket specific to the CTSB structure. CST3 shifts from an inhibitor to an activator of CTSB and therefore fuels the intrapancreatic protease cascade during the onset of AP.

Date: 2025
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DOI: 10.1038/s41467-025-56875-x

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