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ER stress-associated CTRC mutants decrease stimulated pancreatic zymogen secretion through SIRT2-mediated microtubule

Marcelo G Binker1, Daniel Richards1, Herbert Y Gaisano2

  • 1CBRHC Research Center, Buenos Aires, Argentina.

Biochemical and Biophysical Research Communications
|May 30, 2015
PubMed
Summary

Hereditary pancreatitis-linked Chymotrypsin C (CTRC) mutations cause endoplasmic reticulum (ER) stress, impairing pancreatic zymogen secretion. Inhibiting SIRT2 restores secretion by affecting microtubule stability, but not CTRC mutant secretion.

Keywords:
CTRCER stressMicrotubule dysregulationPancreatic zymogen secretionSIRT2

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Area of Science:

  • Cell biology
  • Gastroenterology
  • Biochemistry

Background:

  • Pancreatitis involves pancreatic autodigestion, with impaired zymogen secretion and protease activation being key events.
  • Chymotrypsin C (CTRC) normally limits protease activity; mutations are linked to hereditary pancreatitis.
  • ER stress and altered microtubule stability are implicated in pancreatic dysfunction.

Purpose of the Study:

  • To investigate the mechanism by which CTRC mutants associated with ER stress impair pancreatic acinar cell secretion.
  • To determine the role of SIRT2 and tubulin acetylation in CTRC-mutant-induced secretion defects.

Main Methods:

  • Expression of wild-type and mutant CTRC in rat pancreatic acinar cells (AR42J) and isolated mouse pancreatic acini.
  • Measurement of amylase secretion, tubulin acetylation, SIRT2 levels, and SIRT2 phosphorylation.
  • Pharmacological inhibition of SIRT2.

Main Results:

  • CTRC mutants (p.A73T, p.G61R) caused ER stress and reduced amylase secretion.
  • Mutant expression decreased tubulin acetylation by increasing SIRT2 levels and phosphorylation.
  • SIRT2 inhibition restored tubulin acetylation and amylase secretion, but not secretion of the CTRC mutants.
  • Secretion inhibition correlated with the degree of ER stress.

Conclusions:

  • CTRC variants causing ER stress inhibit pancreatic zymogen secretion by disrupting microtubule stability via SIRT2.
  • SIRT2 is a key mediator linking ER stress to impaired secretion in pancreatitis.
  • Targeting SIRT2 may offer therapeutic potential for pancreatitis, though not directly for mutant CTRC clearance.