Elevated expression of Paneth cell CRS4C in ileitis-prone SAMP1/YitFc mice: Regional distribution, subcellular localization, and mechanism of action

Michael T. Shanahan, Alda Vidrich, Yoshinori Shirafuji, Claire L. Dubois, Agnes Henschen-Edman, Susan J. Hagen, Steven Cohn, André J. Ouellette

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Paneth cells at the base of small intestinal crypts of Lieberkühn secrete host defense peptides and proteins, including α-defensins, as mediators of innate immunity. Mouse Paneth cells also express α-defensin-related Defcr-rs genes that code for cysteine-rich sequence 4C (CRS4C) peptides that have a unique CPX triplet repeat motif. In ileitis-prone SAMP1/YitFc mice, Paneth cell levels of CRS4C mRNAs and peptides are induced more than a 1000-fold relative to non-prone strains as early as 4 weeks of age, with the mRNA and peptide levels highest in distal ileum and below detection in duodenum. CRS4C-1 peptides are found exclusively in Paneth cells where they occur only in dense core granules and thus are secreted to function in the intestinal lumen. CRS4C bactericidal peptide activity is membrane-disruptive in that it permeabilizes Escherichia coli and induces rapid microbial cell K + efflux, but in a manner different from mouse α-defensin cryptdin-4. In in vitro studies, inactive pro-CRS4C-1 is converted to bactericidal CRS4C-1 peptide by matrix metalloproteinase-7 (MMP-7) proteolysis of the precursor proregion at the same residue positions that MMP-7 activates mouse pro-α-defensins. The absence of processed CRS4C in protein extracts of MMP-7-null mouse ileum demonstrates the in vivo requirement for intracellular MMP-7 in pro-CRS4C processing.

Original languageEnglish (US)
Pages (from-to)7493-7504
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number10
DOIs
StatePublished - Mar 5 2010
Externally publishedYes

Fingerprint

Ileitis
Paneth Cells
Cysteine
Matrix Metalloproteinase 7
Defensins
Peptides
Ileum
Proteolysis
Trinucleotide Repeats
Messenger RNA
Duodenum
Innate Immunity
Escherichia coli
Proteins
Genes
Membranes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shanahan, M. T., Vidrich, A., Shirafuji, Y., Dubois, C. L., Henschen-Edman, A., Hagen, S. J., ... Ouellette, A. J. (2010). Elevated expression of Paneth cell CRS4C in ileitis-prone SAMP1/YitFc mice: Regional distribution, subcellular localization, and mechanism of action. Journal of Biological Chemistry, 285(10), 7493-7504. https://doi.org/10.1074/jbc.M109.083220

Elevated expression of Paneth cell CRS4C in ileitis-prone SAMP1/YitFc mice : Regional distribution, subcellular localization, and mechanism of action. / Shanahan, Michael T.; Vidrich, Alda; Shirafuji, Yoshinori; Dubois, Claire L.; Henschen-Edman, Agnes; Hagen, Susan J.; Cohn, Steven; Ouellette, André J.

In: Journal of Biological Chemistry, Vol. 285, No. 10, 05.03.2010, p. 7493-7504.

Research output: Contribution to journalArticle

Shanahan, Michael T. ; Vidrich, Alda ; Shirafuji, Yoshinori ; Dubois, Claire L. ; Henschen-Edman, Agnes ; Hagen, Susan J. ; Cohn, Steven ; Ouellette, André J. / Elevated expression of Paneth cell CRS4C in ileitis-prone SAMP1/YitFc mice : Regional distribution, subcellular localization, and mechanism of action. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 10. pp. 7493-7504.
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