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Papers In Press, published online ahead of print February 26, 2002
Immunologie Virale, Institut Pasteur, 75724, Paris Cedex 15
Corresponding Author: farenzan{at}pasteur.fr
Activation of CXCR4 by the CXC chemokine 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 a SDF-1 fragment that is deleted from amino-terminal residues Lys1-Pro2-Val3, as characterised by mass spectometry analysis. The proteolysed 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 MeOSuc-Ala-Ala-Pro-Val-CMK, 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.
J. Biol. Chem, 10.1074/jbc.M111388200
Submitted on November 29, 2001
Revised on February 26, 2002
Accepted on February 26, 2002
Leukocyte elastase negatively regulates stromal cell-derived factor-1 (SDF-1)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4
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