Heparan Sulfate/Heparin Oligosaccharides Protect Stromal Cell-derived Factor-1 (SDF-1)/CXCL12 against Proteolysis Induced by CD26/Dipeptidyl Peptidase IV

• Published in: The Journal of biological chemistry 2004-10, Vol.279 (42), p.43854-43860
• Main Authors: Sadir, Rabia, Imberty, Anne, Baleux, Françoise, Lortat-Jacob, Hugues
• Format: Article
• Language: English
• Subjects: Antigens, CD; Antigens, CD - metabolism; Antigens, CD26; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Membrane - metabolism; Chemokine CXCL12; Chemokines, CXC; Chemokines, CXC - chemistry; Chemokines, CXC - metabolism; Dipeptidyl Peptidase 4 - metabolism; Heparin; Heparin - chemistry; Heparin - pharmacology; Heparitin Sulfate; Heparitin Sulfate - chemistry; Heparitin Sulfate - pharmacology; Humans; Kinetics; Models, Molecular; Oligosaccharides; Oligosaccharides - pharmacology; Protein Conformation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M405392200

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that is constitutively expressed in most tissues and displayed on the cell surface in association with heparan sulfate (HS). Its numerous biological effects are mediated by a specific G protein-coupled receptor, CXCR4. A number of cells inactivate SDF-1 by specific processing of the N-terminal domain of the chemokine. In particular, CD26/dipeptidyl peptidase IV (DPP IV), a serine protease that co-distributes with CXCR4 at the cell surface, mediates the selective removal of the N-terminal dipeptide of SDF-1. We report here that heparin and HS specifically prevent the processing of SDF-1 by DPP IV expressed by Caco-2 cells. The level of processing increases with the level of differentiation of these cells, which correlates with an increase of DPP IV activity. A mutant SDF-1 that does not interact with HS is readily cleaved by DPP IV, a process that is not inhibited by HS, demonstrating that a productive interaction between HS and SDF-1 is required for the protection to take place. Moreover, we found that protection depends on the degree of polymerization of the HS sulfated S-domains. Finally a structural model of SDF-1, in complex with HS oligosaccharides of defined length, rationalizes the experimental data. The mechanisms by which HS regulates SDF-1 may thus include, in addition to its ability to locally concentrate the chemokine at the cell surface, a control of selective protease cleavage events that directly affect the chemokine activity.