Reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix.
Lysyl hydroxylase 3 (LH3) is a multifunctional enzyme possessing lysyl hydroxylase, collagen galactosyltransferase, and glucosyltransferase (GGT) activities. We report here an important role for LH3 in the organization of the extracellular matrix (ECM) and cytoskeleton. Deposition of ECM was affected in heterozygous LH3 knock-out mouse embryonic fibroblasts (MEF(+/-)) and in skin fibroblasts collected from a member of a Finnish epidermolysis bullosa simplex (EBS) family known to be deficient in GGT activity. We show the GGT deficiency to be due to a transcriptional defect in one LH3 allele. The ECM abnormalities also lead to defects in the arrangement of the cytoskeleton in both cell lines. Ultrastructural abnormalities were observed in the skin of heterozygous LH3 knock-out mice indicating that even a moderate decrease in LH3 has deleterious consequences in vivo. The LH3 null allele in the EBS family member and the resulting abnormalities in the organization of the extracellular matrix, similar to those found in MEF(+/-), may explain the correlation between the severity of the phenotype and the decrease in GGT activity reported in this family.
Risteli
Maija
M
Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
Ruotsalainen
Heli
H
Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
Salo
Antti M
AM
Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
Sormunen
Raija
R
Department of Pathology, Biocenter Oulu, P.O. Box 5000, University of Oulu, FI-90014 Oulu, Finland.
Sipilä
Laura
L
Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland.
Baker
Naomi L
NL
Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Lamandé
Shireen R
SR
Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Vimpari-Kauppinen
Leena
L
Dermatology Clinic, Kainuu Central Hospital, 87140 Kajaani, Finland.
Myllylä
Raili
R
Departments of Biochemistry, P.O. Box 3000, University of Oulu, FI-90014 Oulu, Finland. Electronic address: raili.myllyla@oulu.fi.
D000199:Actins / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D024142:Collagen Type VI / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D016110:Epidermolysis Bullosa Simplex / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D000199:Actins; D024042:Collagen Type I; D024142:Collagen Type VI; D005353:Fibronectins; D014404:Tubulin; D014746:Vimentin; C510730:lysyl hydroxylase 3, mouse; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D005964:Glucosyltransferases
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