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

Wenke Seifert, Jirko Kühnisch, Tanja Maritzen, Stefanie Lommatzsch, Hans Christian Hennies, Sebastian Bachmann, Denise Horn, Volker Haucke

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 Golgienriched 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.

LanguageEnglish
Pages3349-3358
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number6
Early online date9 Dec 2014
DOIs
Publication statusPublished - 6 Feb 2015
Externally publishedYes

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Monomeric GTP-Binding Proteins
Golgi Apparatus
Membrane Lipids
Scaffolds
Neurons
Brain
Proteins
Genes
Retinal Dystrophies
Microcephaly
RNA Interference
Intellectual Disability
Experiments
Maintenance
Cohen syndrome
Neuronal Outgrowth
Mutation

Cite this

Seifert, Wenke ; Kühnisch, Jirko ; Maritzen, Tanja ; Lommatzsch, Stefanie ; Hennies, Hans Christian ; Bachmann, Sebastian ; Horn, Denise ; Haucke, Volker. / Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 6. pp. 3349-3358.
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Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. / Seifert, Wenke; Kühnisch, Jirko; Maritzen, Tanja; Lommatzsch, Stefanie; Hennies, Hans Christian; Bachmann, Sebastian; Horn, Denise; Haucke, Volker.

In: Journal of Biological Chemistry, Vol. 290, No. 6, 06.02.2015, p. 3349-3358.

Research output: Contribution to journalArticle

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AU - Seifert, Wenke

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AU - Lommatzsch, Stefanie

AU - Hennies, Hans Christian

AU - Bachmann, Sebastian

AU - Horn, Denise

AU - Haucke, Volker

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