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J. Biol. Chem., Vol. 282, Issue 46, 33381-33388, November 16, 2007

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Secretion and Assembly of Type IV and VI Collagens Depend on Glycosylation of Hydroxylysines^*

Laura Sipilä, Heli Ruotsalainen, Raija Sormunen^¶, Naomi L. Baker^||, Shireen R. Lamandé^||, Miia Vapola, Chunguang Wang, Yoshikazu Sado^**, Attila Aszodi, and Raili Myllylä¹

From the Biocenter Oulu and the Departments of Biochemistry and ^¶Pathology, University of Oulu, FI-90014 Oulu, Finland, the ^||Murdoch Childrens Research Institute and Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, Victoria 3052, Australia, the ^**Division of Immunology, Shigei Medical Research Institute, 2117 Yamada, Okayama 701-0202, Japan, and the Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany

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.

Received for publication, May 22, 2007 , and in revised form, September 12, 2007.

^* This work was supported by grants from the Research Council for Natural Sciences of the Academy of Finland, the Sigrid Juselius Foundation, and Biocenter Oulu. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, University of Oulu, P. O. Box 3000, FI-90014 Oulu, Finland. Tel.: 358-8-553-1160; Fax: 358-8-553-1141; E-mail: raili.myllyla{at}oulu.fi.

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