Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.
Most lysines in type IV and VI collagens are hydroxylated and glycosylated, but the functions of these unique galactosylhydroxylysyl and glucosylgalactosylhydroxylysyl residues are poorly understood. The formation of glycosylated hydroxylysines is catalyzed by multifunctional lysyl hydroxylase 3 (LH3) in vivo, and we have used LH3-manipulated mice and cells as models to study the function of these carbohydrates. These hydroxylysine-linked carbohydrates were shown recently to be indispensable for the formation of basement membranes (Ruotsalainen, H., Sipilä, L., Vapola, M., Sormunen, R., Salo, A. M., Uitto, L., Mercer, D. K., Robins, S. P., Risteli, M., Aszodi, A., Fässler, R., and Myllylä, R. (2006) J. Cell Sci. 119, 625-635). Analysis of LH3 knock-out embryos and cells in this work indicated that loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens. Mice lacking the LH activity of LH3 produced slightly underglycosylated type IV and VI collagens with abnormal distribution. The altered distribution and aggregation of type VI collagen led to similar ultrastructural alterations in muscle to those detected in collagen VI knockout and some Ullrich congenital muscular dystrophy patients. Our results provide new information about the function of hydroxylysine-linked carbohydrates of collagens, indicating that they play an important role in the secretion, assembly, and distribution of highly glycosylated collagen types.
Sipilä
Laura
L
Department of Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland; Department of Biochemistry, University of Oulu, Oulu, FI-90014, Finland.
Ruotsalainen
Heli
H
Department of Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland; Department of Biochemistry, University of Oulu, Oulu, FI-90014, Finland.
Sormunen
Raija
R
Department of Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland; Department of Pathology, University of Oulu, FI-90014 Oulu, Finland.
Baker
Naomi L
NL
Murdoch Childrens Research Institute and Department of Paediatrics, Royal Childrenŉs Hospital, University of Melbourne, Parkville, Victoria 3052, Australia.
Lamandé
Shireen R
SR
Murdoch Childrens Research Institute and Department of Paediatrics, Royal Childrenŉs Hospital, University of Melbourne, Parkville, Victoria 3052, Australia.
Vapola
Miia
M
Department of Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland; Department of Biochemistry, University of Oulu, Oulu, FI-90014, Finland.
Wang
Chunguang
C
Department of Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland; Department of Biochemistry, University of Oulu, Oulu, FI-90014, Finland.
Sado
Yoshikazu
Y
Division of Immunology, Shigei Medical Research Institute, 2117 Yamada, Okayama 701-0202, Japan.
Aszodi
Attila
A
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Myllylä
Raili
R
Department of Biocenter Oulu, University of Oulu, Oulu, FI-90014, Finland; Department of Biochemistry, University of Oulu, Oulu, FI-90014, Finland. Electronic address: raili.myllyla@oulu.fi.
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002241:Carbohydrates / Q000737:chemistry; D003094:Collagen / Q000737:chemistry; D024141:Collagen Type IV / Q000737:chemistry*; D024142:Collagen Type VI / Q000737:chemistry*; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006579:Heterozygote; D006901:Hydroxylysine / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation
D002241:Carbohydrates; D024141:Collagen Type IV; D024142:Collagen Type VI; D006901:Hydroxylysine; D003094:Collagen