McKown, R L, et al. A Cleavage Potentiated Fragment of Tear Lacritin Is Bactericidal. J Biol Chem, 2014.


Antimicrobial peptides are important as the first line of innate defense, through their tendency to disrupt bacterial membranes or intracellular pathways and potentially as the next generation of antibiotics. How they protect wet epithelia is not entirely clear, with most individually inactive under physiological conditions and many preferentially targeting Gram-positive bacteria. Tears covering the surface of the eye are bactericidal for Gram positive and negative bacteria. Here we narrow much of the bactericidal activity to a latent C-terminal fragment in the prosecretory mitogen lacritin, and report that the mechanism combines membrane permeabilization, with rapid metabolic changes including reduced levels of dephosphocoenzyme A, spermidine, putrescine and phosphatidylethanolamines, and elevated alanine, leucine, phenylalanine, tryptophan, proline, glycine, lysine, serine, glutamate, cadaverine and pyrophosphate. Thus, death by metabolic stress parallels cellular attempts to survive. Cleavage dependent appearance of the C-terminal cationic amphipathic alpha-helix is inducible within hours by S. epidermidis, and slowly by another mechanism, in a chymotrypsin or leupeptin protease inhibitable manner. Although bactericidal at low micromolar levels, within a biphasic 1 - 10 nM dose optimum the same domain is mitogenic and cytoprotective for epithelia via a syndecan-1 targeting mechanism dependent on heparanase. Thus the C-terminus of lacritin is multifunctional by dose and proteolytic processing, and appears to play a key role in the innate protection of the eye - with wider potential benefit elsewhere as lacritin flows from exocrine secretory cells.

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