title: Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth.
abstract: Postnatal microcephaly, intellectual disability, and progressive retinal dystrophy are major features of autosomal recessive Cohen syndrome, which is caused by mutations in the gene COH1 (VPS13B). We have recently identified COH1 as a Golgi-enriched scaffold protein that contributes to the structural maintenance and function of the Golgi complex. Here, we show that association of COH1 with the Golgi complex depends on the small GTPase RAB6. RNAi-mediated knockdown of RAB6A/A' prevents the localization of COH1 to the Golgi complex. Expression of the constitutively inactive RAB6_T27N mutant led to an increased solubilization of COH1 from lipid membrane preparations. Co-IP experiments confirmed the physical interaction of COH1 with RAB6 that preferentially occurred with the constitutively active RAB6_Q72L mutants. Depletion of COH1 in primary neurons negatively interfered with neurite outgrowth, indicating a causal link between the integrity of the Golgi complex and axonal outgrowth. We conclude that COH1 is a RAB6 effector protein and that reduced brain size in Cohen syndrome patients likely results from impaired COH1 function at the Golgi complex, causing decreased neuritogenesis.
authors.affiliation: From the Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany, wenke.seifert@charite.de.
authors.forename: Wenke
authors.initials: W
authors.lastname: Seifert
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany, Max-Planck-Institute for Molecular Genetics, FG Development and Disease, 14195 Berlin, Germany.
authors.forename: Jirko
authors.initials: J
authors.lastname: Kühnisch
authors.affiliation: Department of Molecular Pharmacology and Cell Biology, Leibniz-Institute for Molecular Pharmacology, 13125 Berlin, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Maritzen
authors.affiliation: From the Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lommatzsch
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany, and the Division of Human Genetics, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.affiliation: From the Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Department of Molecular Pharmacology and Cell Biology, Leibniz-Institute for Molecular Pharmacology, 13125 Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016501:Neurites / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C094135:Rab6 protein; C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins
keywords: COH1; Cohen Syndrome; GTPase; Genetic Disease; Golgi; Neurite Outgrowth; Protein-Protein Interaction; RAB6