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J. Biol. Chem., Vol. 277, Issue 18, 15677-15689, May 3, 2002
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From the a Unité d'Immunologie Virale,
d Unité de Chimie Organique, e Unité de
Défense Innée et Inflammation/INSERM U485 de l'Institut
Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, g INRA,
Station de Pathologie Végétale, BP81 33883 Villeneuve
d'Ornon, and h Unité de Neurovirologie et
Régénération du Système Nerveux de l'Institut
Pasteur, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France
Activation of CXCR4 by the CXC chemokine stromal
cell-derived factor-1 (SDF-1) requires interaction of the
amino-terminal domains of both molecules. We report that proteinases
released from either mononucleated blood cells or polymorphonuclear
neutrophils degranulated by inflammatory stimuli generate an SDF-1
fragment that is deleted from amino-terminal residues
Lys1-Pro2-Val3, as
characterized by mass spectrometry analysis. The proteolyzed chemokine fails to induce agonistic functions and is unable to prevent
the fusogenic capacity of CXCR4-tropic human immunodeficiency viruses. Furthermore, we observed that exposure of CXCR4-expressing cells to leukocyte proteinases results in the proteolysis of the extracellular amino-terminal domain of the receptor, as assessed by
flow cytometry analysis and electrophoretic separation of
immunoprecipitated CXCR4. Blockade of SDF-1 and CXCR4 proteolysis by
the specific leukocyte elastase inhibitor,
N-methoxysuccinyl-alanine-alanine-proline-valine-chloromethyl ketone, identified elastase as the major enzyme among
leukocyte-secreted proteinases that accounts for inactivation of both
SDF-1 and CXCR4. Indeed, purified leukocyte elastase generated in
either SDF-1 or CXCR4 a pattern of cleavage indistinguishable from that
observed with leukocyte-secreted proteinases. Our findings suggest that elastase-mediated proteolysis of SDF-1/CXCR4 is part of a mechanism regulating their biological functions in both homeostatic and pathologic processes.
Leukocyte Elastase Negatively Regulates Stromal Cell-derived
Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal
Processing of SDF-1 and CXCR4*
*
This work was supported in part by grants from ANRS
(France) and Ensemble Contre le SIDA "SIDACTION" (France).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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