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

Lim, Jean K
Lu, Wuyuan
DeVico, Anthony L
Published in Journal of Leukocyte Biology. 2006, vol. 80, no. 6, p. 1395-404
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, 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.
Keywords Antibodies/pharmacologyAntiviral Agents/metabolism/pharmacology/therapeutic useCathepsin GCathepsins/antagonists & inhibitors/metabolismChemokine CCL5/analogs & derivatives/metabolism/pharmacology/therapeutic useChemotaxis/drug effectsHIV Infections/metabolism/prevention & controlHumansNeutrophils/enzymologyProtein ProcessingPost-Translational/drug effectsProteins/pharmacologyReceptorsCCR5/metabolismRecombinant Proteins/metabolism/pharmacology/therapeutic useSerine Endopeptidases/metabolismSerine Proteinase Inhibitors/pharmacology
PMID: 16963625
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Research group HIV (835)
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LIM, Jean K et al. N-terminal proteolytic processing by cathepsin G converts RANTES/CCL5 and related analogs into a truncated 4-68 variant. In: Journal of Leukocyte Biology, 2006, vol. 80, n° 6, p. 1395-404. doi: 10.1189/jlb.0406290 https://archive-ouverte.unige.ch/unige:26030

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Deposited on : 2013-01-30

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