Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity.
The chemokine stromal-derived factor-1 (SDF-1), which is constitutively expressed in most tissues as SDF-1alpha and SDF-1beta resulting from alternative gene splicing, regulates hematopoiesis, lymphocyte homing, B-lineage cell growth, and angiogenesis. Because SDF-1alpha and SDF-1beta are constitutively and ubiquitously expressed, their degradation must serve an important regulatory role. Here we show that SDF-1alpha and SDF-1beta are secreted as full-length molecules. When exposed to human serum, full-length SDF-1alpha (1-68) undergoes processing first at the COOH terminus to produce SDF-1alpha 1-67 and then at the NH2 terminus to produce SDF-1alpha 3-67. By contrast, full-length SDF-1beta (1-72) is processed only at the NH2 terminus to produce SDF-1beta 3-72. CD26/dipeptidyl peptidase is responsible for serum cleavage of SDF-1alpha and SDF-1beta at the NH2 terminus. Serum processing of SDF-1alpha at the COOH terminus, which has not been previously reported, reduces the ability of the polypeptide to bind to heparin and to cells and to stimulate B-cell proliferation and chemotaxis. The additional processing at the NH2 terminus renders both forms of SDF-1 unable to bind to heparin and to activate cells. The differential processing of SDF-1alpha and SDF-1beta provides biologic significance to the existence of 2 splice forms of the chemokine and adds a tool to precisely regulate SDF-1's biologic activity by changes in specific activity.
De La Luz Sierra
Maria
M
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Yang
Fuquan
F
Narazaki
Masashi
M
Salvucci
Ombretta
O
Davis
David
D
Yarchoan
Robert
R
Zhang
Hongwei H
HH
Fales
Henry
H
Tosato
Giovanna
G
D017398:Alternative Splicing; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000235:genetics* / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D011994:Recombinant Proteins / Q000097:blood / Q000276:immunology; D017384:Sequence Deletion; D021241:Spectrometry, Mass, Electrospray Ionization; D014471:Umbilical Veins
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016207:Cytokines; D011994:Recombinant Proteins