title: The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface.
abstract: Dominant or recessive mutations in the progressive ankylosis gene ANKH have been linked to familial chondrocalcinosis (CCAL2), craniometaphyseal dysplasia (CMD), mental retardation, deafness and ankylosis syndrome (MRDA). The function of the encoded membrane protein ANK in cellular compartments other than the plasma membrane is unknown. Here, we show that ANK localizes to the trans-Golgi network (TGN), clathrin-coated vesicles and the plasma membrane. ANK functionally interacts with clathrin and clathrin associated adaptor protein (AP) complexes as loss of either protein causes ANK dispersion from the TGN to cytoplasmic endosome-like puncta. Consistent with its subcellular localization, loss of ANK results in reduced formation of tubular membrane carriers from the TGN, perinuclear accumulation of early endosomes and impaired transferrin endocytosis. Our data indicate that clathrin/AP-mediated cycling of ANK between the TGN, endosomes, and the cell surface regulates membrane traffic at the TGN/endosomal interface. These findings suggest that dysfunction of Golgi-endosomal membrane traffic may contribute to ANKH-associated pathologies.
authors.affiliation: Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Wenke
authors.initials: W
authors.lastname: Seifert
authors.affiliation: Department of Molecular Pharmacology and Cell Biology, Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: York
authors.initials: Y
authors.lastname: Posor
authors.affiliation: Department of Cellular Biochemistry, Universitätsmedizin Georg-August University, Göttingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schu
authors.affiliation: College of Health and Life Sciences, Brunel University, Uxbridge, United Kingdom.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Stenbeck
authors.affiliation: Institute for Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Germany.|FG Development and Disease, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Experimental and Clinical Research Center (ECRC) | Max-Delbrück-Centrum for Molecular Medicine (MDC), Charité - Universitätsmedizin Berlin, Berlin, Germany.|Department of Pediatric Cardiology, Charité - Universitätsmedizin Berlin, Germany and.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klaassen
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Molecular Pharmacology and Cell Biology, Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
authors.affiliation: Institute for Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Germany.|FG Development and Disease, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Institute for Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Germany jirko.kuehnisch@mdc-berlin.de.|FG Development and Disease, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.|Experimental and Clinical Research Center (ECRC) | Max-Delbrück-Centrum for Molecular Medicine (MDC), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jirko
authors.initials: J
authors.lastname: Kühnisch
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000378:metabolism*; D004705:Endocytosis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D028061:Phosphate Transport Proteins / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: C498770:ANKH protein, human; D002966:Clathrin; D028061:Phosphate Transport Proteins; D014168:Transferrin