Loss of chymotrypsin-like protease (CTRL) alters intrapancreatic protease activation but not pancreatitis severity in mice.
Acute Disease
Animals
Biopsy
Cell Line
Chymotrypsin
/ metabolism
Disease Models, Animal
Enzyme Activation
Gene Expression
Humans
Immunohistochemistry
Mice
Mice, Knockout
Pancreas
/ enzymology
Pancreatitis
/ etiology
Peroxidase
/ genetics
Serine Endopeptidases
/ deficiency
Severity of Illness Index
Trypsin
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 07 2020
16 07 2020
Historique:
received:
23
03
2020
accepted:
22
06
2020
entrez:
18
7
2020
pubmed:
18
7
2020
medline:
15
12
2020
Statut:
epublish
Résumé
The digestive enzyme chymotrypsin protects the pancreas against pancreatitis by reducing harmful trypsin activity. Genetic deficiency in chymotrypsin increases pancreatitis risk in humans and pancreatitis severity in mice. Pancreatic chymotrypsin is produced in multiple isoforms including chymotrypsin B1, B2, C and chymotrypsin-like protease (CTRL). Here we investigated the role of CTRL in cerulein-induced pancreatitis in mice. Biochemical experiments with recombinant mouse enzymes demonstrated that CTRL cleaved trypsinogens and suppressed trypsin activation. We generated a novel CTRL-deficient strain (Ctrl-KO) using CRISPR-Cas9 genome engineering. Homozygous Ctrl-KO mice expressed no detectable CTRL protein in the pancreas. Remarkably, the total chymotrypsinogen content in Ctrl-KO mice was barely reduced indicating that CTRL is a low-abundance isoform. When given cerulein, Ctrl-KO mice exhibited lower intrapancreatic chymotrypsin activation and a trend for higher trypsin activation, compared with C57BL/6N mice. Despite the altered protease activation, severity of cerulein-induced acute pancreatitis was similar in Ctrl-KO and C57BL/6N mice. We conclude that CTRL is a minor chymotrypsin isoform that plays no significant role in cerulein-induced pancreatitis in mice.
Identifiants
pubmed: 32678161
doi: 10.1038/s41598-020-68616-9
pii: 10.1038/s41598-020-68616-9
pmc: PMC7366634
doi:
Substances chimiques
Peroxidase
EC 1.11.1.7
Serine Endopeptidases
EC 3.4.21.-
Chymotrypsin
EC 3.4.21.1
Trypsin
EC 3.4.21.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11731Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK058088
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK082412
Pays : United States
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