Coordinated roles of ST3Gal-VI and ST3Gal-IV sialyltransferases in the synthesis of selectin ligands.
Binding of selectins to their glycan ligands is a prerequisite for successful leukocyte trafficking. During synthesis and transport through the secretory pathway, selectin ligands are constructed with the participation of one or more sialyltransferases of the ST3Gal subfamily. Previous studies established that ST3Gal-IV only partially contributes to selectin ligand formation, indicating that other ST3Gal-sialyltransferases are involved. By generating and analyzing St3gal6-null mice and St3gal4/St3gal6 double-deficient mice, in the present study, we found that binding of E- and P-selectin to neutrophils and L-selectin binding to lymph node high endothelial venules is reduced in the absence of ST3Gal-VI and to a greater extent in double-deficient mice. In an ex vivo flow chamber assay, P- and E-selectin-dependent leukocyte rolling was mildly reduced in St3gal6-null mice and more severely in double-deficient mice. In inflamed cremaster muscle venules of St3gal6-null mice, we found impaired P-selectin-dependent, but not E-selectin-dependent leukocyte rolling, whereas in double-deficient mice, E-selectin-dependent rolling was almost completely absent. Furthermore, neutrophil recruitment into the inflamed peritoneal cavity and lymphocyte homing to secondary lymphoid organs were impaired in St3gal6-null mice and more severely in double-deficient mice. The results of the present study demonstrate the coordinated participation of both ST3Gal-VI and ST3Gal-IV in the synthesis of functional selectin ligands.
Center for Nanomedicine, Sanford-Burnham Medical Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
Won Ho
WH
Yang
Claudia
C
Nussbaum
Prabhjit K
PK
Grewal
Jamey D
JD
Marth
Markus
M
Sperandio
D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000502:physiology; D019040:E-Selectin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006487:Hemostasis / Q000235:genetics; D036904:Leukocyte Rolling / Q000235:genetics; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D019007:P-Selectin / Q000378:metabolism; D011485:Protein Binding; D012039:Regional Blood Flow / Q000235:genetics / Q000502:physiology; D019087:Selectins / Q000096:biosynthesis* / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014018:Tissue Distribution; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D019040:E-Selectin; D008024:Ligands; D019007:P-Selectin; D019087:Selectins; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase