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Division of Dermatology,
Division of Pulmonary Medicine,
Department of Microbiology and Immunology, and
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Molecular Biology Institute, University of California School of Medicine, Los Angeles, CA 90095;
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Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461;
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Office of the Dean, Harvard School of Public Health, Boston, MA 02115;
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Division of Immunology and Transplantation Biology, Department of Pediatrics, Stanford University, Stanford, CA, 94305; and
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Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
Granulysin, a protein located in the acidic granules of human NK
cells and cytotoxic T cells, has antimicrobial activity against a broad
spectrum of microbial pathogens. A predicted model generated from the
nuclear magnetic resonance structure of a related protein, NK lysin,
suggested that granulysin contains a four 
helical bundle motif,
with the helices enriched for positively charged amino acids,
including arginine and lysine residues. Denaturation of the polypeptide
reduced the helical content from 49 to 18% resulted in complete
inhibition of antimicrobial activity. Chemical modification of the
arginine, but not the lysine, residues also blocked the antimicrobial
activity and interfered with the ability of granulysin to adhere to
Escherichia coli and Mycobacterium
tuberculosis. Granulysin increased the permeability of
bacterial membranes, as judged by its ability to allow access of
cytosolic ß-galactosidase to its impermeant substrate. By electron
microscopy, granulysin triggered fluid accumulation in the periplasm of
M. tuberculosis, consistent with osmotic perturbation.
These data suggest that the ability of granulysin to kill microbial
pathogens is dependent on direct interaction with the microbial cell
wall and/or membrane, leading to increased permeability and
lysis.
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