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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0406290

Received for publication April 25, 2006.
Revised July 4, 2006.
Accepted for publication July 20, 2006.

Article

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

Jean K. Lim *{dagger}, Wuyuan Lu *, Oliver Hartley {ddagger}, and Anthony L. DeVico *@

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

@ To whom correspondence should be addressed. E-mail: devico{at}umbi.umd.edu.


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Abstract

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, anticathepsin 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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