Elevated expression of Paneth cell CRS4C in ileitis-prone SAMP1/YitFc mice: regional distribution, subcellular localization, and mechanism of action.
Paneth cells at the base of small intestinal crypts of Lieberkühn secrete host defense peptides and proteins, including alpha-defensins, as mediators of innate immunity. Mouse Paneth cells also express alpha-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 alpha-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-alpha-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.
Shanahan
Michael T
MT
Department of Microbiology and Molecular Genetics, School of Medicine, College of Health Sciences, University of California, Irvine, California 92697-4800, USA.
Vidrich
Alda
A
Shirafuji
Yoshinori
Y
Dubois
Claire L
CL
Henschen-Edman
Agnes
A
Hagen
Susan J
SJ
Cohn
Steven M
SM
Ouellette
André J
AJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D023082:Defensins / Q000235:genetics / Q000378:metabolism*; D007079:Ileitis / Q000378:metabolism*; D007082:Ileum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D019879:Paneth Cells / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism / Q000648:ultrastructure; D014018:Tissue Distribution; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; C092570:CRS4C protein, mouse; D023082:Defensins; D011498:Protein Precursors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D023084:alpha-Defensins; D020783:Matrix Metalloproteinase 7