Initiation of protein O glycosylation by the polypeptide GalNAcT-1 in vascular biology and humoral immunity.
Core-type protein O glycosylation is initiated by polypeptide N-acetylgalactosamine (GalNAc) transferase (ppGalNAcT) activity and produces the covalent linkage of serine and threonine residues of proteins. More than a dozen ppGalNAcTs operate within multicellular organisms, and they differ with respect to expression patterns and substrate selectivity. These distinctive features imply that each ppGalNAcT may differentially modulate regulatory processes in animal development, physiology, and perhaps disease. We found that ppGalNAcT-1 plays key roles in cell and glycoprotein selective functions that modulate the hematopoietic system. Loss of ppGalNAcT-1 activity in the mouse results in a bleeding disorder which tracks with reduced plasma levels of blood coagulation factors V, VII, VIII, IX, X, and XII. ppGalNAcT-1 further supports leukocyte trafficking and residency in normal homeostatic physiology as well as during inflammatory responses, in part by providing a scaffold for the synthesis of selectin ligands expressed by neutrophils and endothelial cells of peripheral lymph nodes. Animals lacking ppGalNAcT-1 are also markedly impaired in immunoglobulin G production, coincident with increased germinal center B-cell apoptosis and reduced levels of plasma B cells. These findings reveal that the initiation of protein O glycosylation by ppGalNAcT-1 provides a distinctive repertoire of advantageous functions that support vascular responses and humoral immunity.
Tenno
Mari
M
Howard Hughes Medical Institute, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Ohtsubo
Kazuaki
K
Hagen
Fred K
FK
Ditto
David
D
Zarbock
Alexander
A
Schaerli
Patrick
P
von Andrian
Ulrich H
UH
Ley
Klaus
K
Le
Dzung
D
Tabak
Lawrence A
LA
Marth
Jamey D
JD
D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology; D001790:Blood Physiological Phenomena; D005854:Germ Cells / Q000201:enzymology; D018858:Germinal Center / Q000201:enzymology; D006031:Glycosylation; D006470:Hemorrhage; D006487:Hemostasis; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D007249:Inflammation / Q000201:enzymology; D007962:Leukocytes / Q000201:enzymology; D008024:Ligands; D008214:Lymphocytes / Q000201:enzymology; D051379:Mice; D016296:Mutagenesis; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology; D021381:Protein Transport; D019087:Selectins / Q000378:metabolism; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D007074:Immunoglobulin G; D008024:Ligands; D017350:N-Acetylgalactosaminyltransferases; D019087:Selectins; D000097763:Polypeptide N-acetylgalactosaminyltransferase