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N‐terminal proteolytic processing by cathepsin G converts RANTES/CCL5 and related analogs into a truncated 4‐68 variant
Author(s) -
Lim Jean K.,
Lu Wuyuan,
Hartley Oliver,
DeVico Anthony L.
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0406290
Subject(s) - cathepsin g , ccl5 , microbiology and biotechnology , biology , cathepsin l1 , cathepsin , cathepsin d , chemotaxis , cathepsin l , cathepsin o , cathepsin h , cathepsin b , chemokine , cathepsin a , elastase , t cell , immunology , biochemistry , receptor , enzyme , immune system , il 2 receptor
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.