title: Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
abstract: Post-translational modifications are necessary for collagen precursor molecules (procollagens) to acquire final shape and function. However, the mechanism and contribution of collagen modifications that occur outside the endoplasmic reticulum and Golgi are not understood. We discovered that VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, also known as PLOD3) into newly identified post-Golgi collagen IV carriers and that VIPAR-dependent sorting is essential for modification of lysines in multiple collagen types. Identification of structural and functional collagen abnormalities in cells and tissues from patients and murine models of the autosomal recessive multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis syndrome caused by VIPAR and VPS33B deficiencies confirmed our findings. Thus, regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis and for the development and function of multiple organs and tissues.
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Blerida
authors.initials: B
authors.lastname: Banushi
authors.affiliation: Department of Biology and Biotechnology, The Armenise-Harvard Laboratory of Structural Biology, University of Pavia, Via Ferrata 9/A - 27100, Pavia, Italy.|Division of Crystal and Structural Chemistry, Department of Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Federico
authors.initials: F
authors.lastname: Forneris
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Straatman-Iwanowska
authors.affiliation: Eastman Dental Institute, University College London, London WC1X 8LD, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Strange
authors.affiliation: Department of Statistical Science, University College London, London WC1E 6BT, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lyne
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Rogerson
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Jemima J
authors.identifier: 0000-0001-5894-7043
authors.initials: JJ
authors.lastname: Burden
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Heywood
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Hanley
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Doykov
authors.affiliation: Centre for Core Biotechnology Services, University of Leicester, Leicester LE1 9HN, UK.
authors.forename: Kornelis R
authors.initials: KR
authors.lastname: Straatman
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Smith
authors.affiliation: Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B152TT, UK.
authors.forename: Danai
authors.initials: D
authors.lastname: Bem
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Janos
authors.identifier: 0000-0002-0149-145X
authors.initials: J
authors.lastname: Kriston-Vizi
authors.affiliation: Department of Pediatric Nephrology, University Hospital Vall d'Hebron, Universitat Autonoma Barcelona, 119-129-08035 Barcelona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Ariceta
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7B, 90220 Oulu, Finland.|Unit of Cancer Research and Translational Medicine, Faculty of Medicine, University of Oulu, Oulu 90014, Finland.|Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu 90029, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Risteli
authors.affiliation: Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu 90029, Finland.|Medical Microbiology and Immunology, Unit of Biomedicine, Faculty of Medicine, University of Oulu, Oulu 90014, Finland.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK.
authors.forename: Rosalyn E
authors.initials: RE
authors.lastname: Ardill
authors.affiliation: Children's Hospital, 61-825 Poznań, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Zaniew
authors.affiliation: Children's Memorial Health Institute, 04-730 Warsaw, 20 Dzieci Polskich Avenue, Poland.
authors.forename: Julita
authors.initials: J
authors.lastname: Latka-Grot
authors.affiliation: Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.affiliation: Institute for Women's Health, University College London, London WC1E 6AU, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Howe
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ferraro
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Asllan
authors.initials: A
authors.lastname: Gjinovci
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Lawrence
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Marsh
authors.affiliation: Department of Statistics, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Girolami
authors.affiliation: Eastman Dental Institute, University College London, London WC1X 8LD, UK.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bozec
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mills
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.|Institute of Child Health, University College London, London WC1N 1EH, UK.|Inherited Metabolic Diseases Unit, Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Paul
authors.identifier: 0000-0002-9712-6122
authors.initials: P
authors.lastname: Gissen
mesh_terms: D000818:Animals; D001176:Arthrogryposis / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D010641:Phenotype; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D033921:Vesicular Transport Proteins; D003094:Collagen; C475767:PLOD3 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D020691:rab GTP-Binding Proteins