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Research Article Free access | 10.1172/JCI118588

Intramolecular inhibition of human defensin HNP-1 by its propiece.

E V Valore, E Martin, S S Harwig, and T Ganz

Will Rogers Institute Pulmonary Research Laboratory, Department of Medicine, UCLA School of Medicine, Los Angeles, California, 90095-1736, USA.

Find articles by Valore, E. in: JCI | PubMed | Google Scholar

Will Rogers Institute Pulmonary Research Laboratory, Department of Medicine, UCLA School of Medicine, Los Angeles, California, 90095-1736, USA.

Find articles by Martin, E. in: JCI | PubMed | Google Scholar

Will Rogers Institute Pulmonary Research Laboratory, Department of Medicine, UCLA School of Medicine, Los Angeles, California, 90095-1736, USA.

Find articles by Harwig, S. in: JCI | PubMed | Google Scholar

Will Rogers Institute Pulmonary Research Laboratory, Department of Medicine, UCLA School of Medicine, Los Angeles, California, 90095-1736, USA.

Find articles by Ganz, T. in: JCI | PubMed | Google Scholar

Published April 1, 1996 - More info

Published in Volume 97, Issue 7 on April 1, 1996
J Clin Invest. 1996;97(7):1624–1629. https://doi.org/10.1172/JCI118588.
© 1996 The American Society for Clinical Investigation
Published April 1, 1996 - Version history
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Abstract

We examined mechanisms that protect host defense cells from their cytotoxic effector molecules. Human neutrophil peptides (HNP) 1-3 are microbicidal and cytotoxic defensins, initially synthesized as 94-amino acid preproHNP(1-94), cotranslationally proteolyzed to proHNP(20-94), then converted by removal of the anionic propiece to mature HNP(65-94)(HNP-1 and -3) and HNP(66-94) (HNP-2). We hypothesized that during synthesis and subcellular sorting the anionic propiece inhibits the cytotoxicity of the cationic defensin. We expressed preproHNP-1 cDNA in recombinant baculovirus-infected insect cells that secreted the normally transient proHNP-1(20-94) into the medium. Cyanogen bromide cleaved proHNP-1(20-94) at the fortuitously located Met64 to yield mature recombinant HNP-1(65-94) and unlinked propiece. Recombinant and native HNP-1 purified from PMN were identical as judged by mass spectrometry, retention time in reverse-phase high performance liquid chromatography, migration on acid-urea polyacrylamide gels, and reaction with a conformation-specific antibody. Recombinant and native HNP-1 had comparable microbicidal activity towards Listeria monocytogenes and were similarly potent in permeabilizing K562 leukemia cells, but proHNP-1(20-94) was virtually inactive in both assays. Addition of unlinked propiece (proHNP-1(20-64) with Met64-->homoserine) inhibited the bactericidal and cell-permeabilizing activity of mature HNP-1 in a dose-dependent manner. Linked, and to a lesser extent unlinked, propiece interfered with the binding of HNP-1 to target cells. The propiece thus acts as an efficient intramolecular inhibitor of defensin HNP-1 cytotoxicity.

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