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J. Biol. Chem., Vol. 277, Issue 7, 5219-5228, February 15, 2002
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From the Departments of Paneth cells in small intestine crypts secrete
microbicidal
Activation of Paneth Cell
-Defensins in Mouse Small
Intestine*
§¶,§,
,,, and§§¶¶
Pathology and
§§ Microbiology and Molecular Genetics, College
of Medicine, University of California, Irvine, California 92697-4800, the Department of Pediatric Surgery,
Karl-Franzens-Universität Graz, Graz A-8036, Austria, the
** Division of Allergy and Pulmonary Medicine, Department of
Pediatrics, Washington University School of Medicine, St. Louis,
Missouri 63110, and the Department of Surgery, Beth
Israel Deaconess Medical Center, Boston, Massachusetts 02115
-defensins, termed cryptdins, as components of enteric
innate immunity. The bactericidal activity of cryptdins requires
proteolytic activation of precursors by matrix metalloproteinase-7
(MMP-7; matrilysin) (Wilson, C. L., Ouellette, A. J.,
Satchell, D. P., Ayabe, T., Lopez-Boado, Y. S., Stratman,
J. L., Hultgren, S. J., Matrisian, L. M., and Parks,
W. C. (1999) Science 286, 113-117). Here, we report
on the intracellular processing of cryptdin proforms in mouse Paneth
cells. Peptide sequencing of MMP-7 digests of purified natural
procryptdins identified conserved cleavage sites in the proregion
between Ser43 and Val44 as well as at the
cryptdin peptide N terminus between Ser58 and
Leu59. Immunostaining co-localized precursor prosegments
and mature cryptdin peptides to Paneth cell granules, providing
evidence of their secretion. Extensive MMP-7-dependent
procryptdin processing occurs in Paneth cells, as shown by Western blot
analyses of intestinal crypt proteins and proteins from
granule-enriched subcellular fractions. The addition of soluble
prosegments to in vitro antimicrobial peptide assays
inhibited the bactericidal activities of cryptdin-3 and -4 in
trans, suggesting possible cytoprotective effects by prosegments prior to secretion. Levels of activated cryptdins were
normal in small bowel of germ-free mice and in sterile implants of
fetal mouse small intestine grown subcutaneously. Thus, the initiation
of procryptdin processing by MMP-7 does not require direct bacterial
exposure, and the basal MMP-7 content of germ-free Paneth cells is
sufficient to process and activate -defensin precursors.
MMP-7-dependent procryptdin activation in vivo
provides mouse Paneth cells with functional peptides for apical
secretion into the small intestine lumen.
*
This work was supported by National Institutes of Health
Grants DK10184 (to D. P. S.), DE14040 (to C. L. W.), DK15681 (to S. J. H.), and DK44632 (to A. J. O.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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