Glycosyltransferase function in core 2-type protein O glycosylation.
Three glycosyltransferases have been identified in mammals that can initiate core 2 protein O glycosylation. Core 2 O-glycans are abundant among glycoproteins but, to date, few functions for these structures have been identified. To investigate the biological roles of core 2 O-glycans, we produced and characterized mice deficient in one or more of the three known glycosyltransferases that generate core 2 O-glycans (C2GnT1, C2GnT2, and C2GnT3). A role for C2GnT1 in selectin ligand formation has been described. We now report that C2GnT2 deficiency impaired the mucosal barrier and increased susceptibility to colitis. C2GnT2 deficiency also reduced immunoglobulin abundance and resulted in the loss of all core 4 O-glycan biosynthetic activity. In contrast, the absence of C2GnT3 altered behavior linked to reduced thyroxine levels in circulation. Remarkably, elimination of all three C2GnTs was permissive of viability and fertility. Core 2 O-glycan structures were reduced among tissues from individual C2GnT deficiencies and completely absent from triply deficient mice. C2GnT deficiency also induced alterations in I-branching, core 1 O-glycan formation, and O mannosylation. Although the absence of C2GnT and C4GnT activities is tolerable in vivo, core 2 O glycosylation exerts a significant influence on O-glycan biosynthesis and is important in multiple physiological processes.
Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Erica L
EL
Stone
Mohd Nazri
MN
Ismail
Seung Ho
SH
Lee
Ying
Y
Luu
Kevin
K
Ramirez
Stuart M
SM
Haslam
Samuel B
SB
Ho
Anne
A
Dell
Minoru
M
Fukuda
Jamey D
JD
Marth
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D006031:Glycosylation; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D011134:Polysaccharides / Q000096:biosynthesis* / Q000737:chemistry; D013974:Thyroxine / Q000378:metabolism; D014018:Tissue Distribution
D007527:Isoenzymes; D011134:Polysaccharides; D017351:N-Acetylglucosaminyltransferases; C117361:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 3; D013974:Thyroxine