2. Academic Validation
  3. Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth

Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth

  • J Biol Chem. 2015 Feb 6;290(6):3349-58. doi: 10.1074/jbc.M114.608174.
Wenke Seifert 1,  Jirko Kühnisch 2,  Tanja Maritzen 3,  Stefanie Lommatzsch 4,  Hans Christian Hennies 5,  Sebastian Bachmann 4,  Denise Horn 6,  Volker Haucke 3
Affiliations

Affiliations

  • 1 From the Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany, wenke.seifert@charite.de.
  • 2 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.
  • 3 Department of Molecular Pharmacology and Cell Biology, Leibniz-Institute for Molecular Pharmacology, 13125 Berlin, Germany.
  • 4 From the Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany.
  • 5 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.
  • 6 Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
PMID: 25492866 DOI: 10.1074/jbc.M114.608174
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.

Keywords

COH1; Cohen Syndrome; GTPase; Genetic Disease; Golgi; Neurite Outgrowth; Protein-Protein Interaction; RAB6.

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