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First published online February 8, 2006
doi: 10.1242/10.1242/jcs.02780

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Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes

Heli Ruotsalainen^1,*, Laura Sipilä^1,*, Miia Vapola¹, Raija Sormunen², Antti M. Salo¹, Lahja Uitto¹, Derry K. Mercer³, Simon P. Robins³, Maija Risteli¹, Attila Aszodi⁴, Reinhard Fässler⁴ and Raili Myllylä^1,

¹ Department of Biochemistry, Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland
² Department of Pathology, Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland
³ Rowell Research Institute, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, UK
⁴ Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany

Author for correspondence (e-mail: raili.myllyla{at}oulu.fi)

Accepted 3 November 2005

Lysyl hydroxylase 3 (LH3) is a multifunctional enzyme possessing lysyl hydroxylase (LH), hydroxylysyl galactosyltransferase (GT) and galactosylhydroxylysyl glucosyltransferase (GGT) activities in vitro. To investigate the in vivo importance of LH3-catalyzed lysine hydroxylation and hydroxylysine-linked glycosylations, three different LH3-manipulated mouse lines were generated. Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung. Analysis of a hypomorphic LH3 mouse line with the same mutation, however, demonstrated that the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5. Strikingly, survival of hypomorphic embryos and the formation of the basement membrane were directly correlated with the level of GGT activity. In addition, an LH3-knockout mouse lacked GGT activity leading to lethality at E9.5. The results confirm that LH3 has LH and GGT activities in vivo, LH3 is the main molecule responsible for GGT activity and that the GGT activity, not the LH activity of LH3, is essential for the formation of the basement membrane. Together our results demonstrate for the first time the importance of hydroxylysine-linked glycosylation for collagens.

Key words: Lysyl hydroxylase, Glycosylation, Basement membrane, Transgenic mouse

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