Sialyltransferase specificity in selectin ligand formation

Author:

Ellies Lesley G.1,Sperandio Markus1,Underhill Gregory H.1,Yousif James1,Smith Michael1,Priatel John J.1,Kansas Geoffrey S.1,Ley Klaus1,Marth Jamey D.1

Affiliation:

1. From the Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, and Howard Hughes Medical Institute, University of California, San Diego; Cardiovascular Research Center and Department of Biomedical Engineering, University of Virginia Health Sciences Center, Charlottesville, VA; Department of Biomedical Engineering and Microbiology-Immunology, Northwestern University Medical School, Chicago, IL.

Abstract

Selectin ligands are glycan structures that participate in leukocyte trafficking and inflammation. At least 6 ST3Gal sialyltransferases (I-VI) have been identified that may contribute to selectin ligand formation. However, it is not known which of these sialyltransferases are involved in vivo and whether they may differentially regulate selectin function. We have produced and characterized mice genetically deficient in ST3Gal-I, ST3Gal-II, ST3Gal-III, and ST3Gal-IV. Unlike mice bearing severe defects in selectin ligand formation, there was no finding of leukocytosis with these single ST3Gal deficiencies. Among neutrophils, only ST3Gal-IV was found to play a role in the synthesis of selectin ligands. In vitro rolling of marrow-derived neutrophils on E- or P-selectins presented by Chinese hamster ovary cells was reduced in the absence of ST3Gal-IV. However, in a tumor necrosis factor α (TNF-α)–induced inflammation model in vivo, no defect among P-selectin ligands was observed. Nevertheless, the number of leukocytes rolling on postcapillary venules in an E-selectin–dependent manner was decreased while E-selectin–dependent rolling velocity was increased. We propose that multiple ST3Gal sialyltransferases contribute to selectin ligand formation, as none of these ST3Gal deficiencies recapitulated the degree of E- and P-selectin ligand deficit observed on neuraminidase treatment of intact neutrophils. Our findings indicate a high degree of functional specificity among sialyltransferases and a substantial role for ST3Gal-IV in selectin ligand formation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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