Regulation of Intestinal α-Defensin Activation by the Metalloproteinase Matrilysin in Innate Host Defense

TLDR

α‑defensin peptides must be activated from precursors to acquire bactericidal activity. Matrilysin localizes with cryptdins in Paneth cell granules and cleaves their pro segments to activate them. Matrilysin‑deficient mice lack mature cryptdins, exhibit reduced antimicrobial activity, and allow greater bacterial survival and virulence, demonstrating that matrilysin is essential for intestinal defense through defensin activation.

Abstract

Precursors of α-defensin peptides require activation for bactericidal activity. In mouse small intestine, matrilysin colocalized with α-defensins (cryptdins) in Paneth cell granules, and in vitro it cleaved the pro segment from cryptdin precursors. Matrilysin-deficient (MAT −/− ) mice lacked mature cryptdins and accumulated precursor molecules. Intestinal peptide preparations from MAT −/− mice had decreased antimicrobial activity. Orally administered bacteria survived in greater numbers and were more virulent in MAT −/− mice than in MAT +/+ mice. Thus, matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.