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

Author

Listed:
  • 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
    University Medicine 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)

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.

Suggested Citation

  • Jana Marielle Modenbach & Christina Möller & Saeedeh Asgarbeik & Norman Geist & Niklas Rimkus & Mark Dörr & Hannes Wolfgramm & Leif Steil & Anne Susemihl & Leonie Graf & Ole Schmöker & Dominique Böttc, 2025. "Biochemical analyses of cystatin-C dimers and cathepsin-B reveals a trypsin-driven feedback mechanism in acute pancreatitis," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56875-x
    DOI: 10.1038/s41467-025-56875-x
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    References listed on IDEAS

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