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Published online before print September 8, 2006

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(Journal of Leukocyte Biology. 2006;80:1395-1404.)
© 2006 by Society for Leukocyte Biology

N-terminal proteolytic processing by cathepsin G converts RANTES/CCL5 and related analogs into a truncated 4-68 variant

Jean K. Lim^*,, Wuyuan Lu^*, Oliver Hartley and Anthony L. DeVico^*,1

^* Institute of Human Virology, University of Maryland Biotechnology Institute, and
Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland, USA; and
Department of Structural Biology and Bioinformatics, Centre Médical Universitaire, Geneva, Switzerland

¹ Correspondence: Institute of Human Virology, University of Maryland, Baltimore, 725 W. Lombard Street, 6th fl., Baltimore, MD 21201, USA. E-mail: devico{at}umbi.umd.edu

N-terminal proteolytic processing modulates the biological activity and receptor specificity of RANTES/CCL5. Previously, we showed that an unidentified protease associated with monocytes and neutrophils digests RANTES into a variant lacking three N-terminal residues (4-68 RANTES). This variant binds CCR5 but exhibits lower chemotactic and antiviral activities than unprocessed RANTES. In this study, we characterize cathepsin G as the enzyme responsible for this processing. Cell-mediated production of the 4-68 variant was abrogated by Eglin C, a leukocyte elastase and cathepsin G inhibitor, but not by the elastase inhibitor elastatinal. Further, anti-cathepsin G antibodies abrogated RANTES digestion in neutrophil cultures. In accordance, reagent cathepsin G specifically digested recombinant RANTES into the 4-68 variant. AOP-RANTES and Met-RANTES were also converted into the 4-68 variant upon exposure to cathepsin G or neutrophils, while PSC-RANTES was resistant to such cleavage. Similarly, macaque cervicovaginal lavage samples digested Met-RANTES and AOP-RANTES, but not PSC-RANTES, into the 4-68 variant and this processing was also inhibited by anti-cathepsin G antibodies. These findings suggest that cathepsin G mediates a novel pathway for regulating RANTES activity and may be relevant to the role of RANTES and its analogs in preventing HIV infection.

Key Words: HIV • microbicide • chemokine • antiviral • neutrophils

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