A Cleavage-potentiated Fragment of Tear Lacritin Is Bactericidal
| Autor: | Rose K. Sia, Kaneil K. Zadrozny, Denise S. Ryan, Andrea M. Deleault, Ronald W. Raab, Gordon W. Laurie, Erin V. Coleman Frazier, Robert L. McKown, Jae K. Lee |
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| Rok vydání: | 2014 |
| Předmět: |
genetic structures
Molecular Sequence Data Antimicrobial peptides medicine.disease_cause complex mixtures Microbiology Biochemistry Serine chemistry.chemical_compound Protein targeting Escherichia coli Staphylococcus epidermidis medicine Humans Amino Acid Sequence Molecular Biology Glycoproteins Serine protease Lacritin biology Leupeptin Cell Biology equipment and supplies eye diseases Immunity Innate Peptide Fragments Recombinant Proteins Protein Structure Tertiary Spermidine chemistry Tears Proteolysis Metabolome Putrescine biology.protein bacteria Antimicrobial Cationic Peptides |
| Zdroj: | Journal of Biological Chemistry. 289:22172-22182 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m114.570143 |
| Popis: | 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 α-helix is inducible within hours by Staphylococcus 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. |
| Databáze: | OpenAIRE |
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