Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1.
Chemokines provide directional cues for leukocyte migration and activation that are essential for normal leukocytic trafficking and for host responses during processes such as inflammation, infection, and cancer. Recently we reported that matrix metalloproteinases (MMPs) modulate the activity of the CC chemokine monocyte chemoattractant protein-3 by selective proteolysis to release the N-terminal tetrapeptide. Here we report the N-terminal processing, also at position 4-5, of the CXC chemokines stromal cell-derived factor (SDF)-1alpha and beta by MMP-2 (gelatinase A). Robustness of the MMP family for chemokine cleavage was revealed from identical cleavage site specificity of MMPs 1, 3, 9, 13, and 14 (MT1-MMP) toward SDF-1; selectivity was indicated by absence of cleavage by MMPs 7 and 8. Efficient cleavage of SDF-1alpha by MMP-2 is the result of a strong interaction with the MMP hemopexin C domain at an exosite that overlaps the monocyte chemoattractant protein-3 binding site. The association of SDF-1alpha with different glycosaminoglycans did not inhibit cleavage. MMP cleavage of SDF-1alpha resulted in loss of binding to its cognate receptor CXCR-4. This was reflected in a loss of chemoattractant activity for CD34(+) hematopoietic progenitor stem cells and pre-B cells, and unlike full-length SDF-1alpha, the MMP-cleaved chemokine was unable to block CXCR-4-dependent human immunodeficiency virus-1 infection of CD4(+) cells. These data suggest that MMPs may be important regulatory proteases in attenuating SDF-1 function and point to a deep convergence of two important networks, chemokines and MMPs, to regulate leukocytic activity in vivo.
McQuibban
G A
GA
Department of Biochemistry and Molecular Biology, Oral Biological and Medical Sciences, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Butler
G S
GS
Gong
J H
JH
Bendall
L
L
Power
C
C
Clark-Lewis
I
I
Overall
C M
CM
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D002633:Chemotaxis; D004797:Enzyme-Linked Immunosorbent Assay; D006466:Hemopexin / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011509:Proteoglycans; D006466:Hemopexin; D020782:Matrix Metalloproteinases