The Guanine nucleotide exchange factor kalirin-7 is a novel synphilin-1 interacting protein and modifies synphilin-1 aggregate transport and formation.
Synphilin-1 has been identified as an interaction partner of α-synuclein, a key protein in the pathogenesis of Parkinson disease (PD). To further explore novel binding partners of synphilin-1, a yeast two hybrid screening was performed and kalirin-7 was identified as a novel interactor. We then investigated the effect of kalirin-7 ... on synphilin-1 aggregate formation. Coexpression of kalirin-7 and synphilin-1 caused a dramatic relocation of synphilin-1 cytoplasmic small inclusions to a single prominent, perinuclear inclusion. These perinuclear inclusions were characterized as being aggresomes according to their colocalization with microtubule organization center markers, and their formation was microtubule-dependent. Furthermore, kalirin-7 increased the susceptibility of synphilin-1 inclusions to be degraded as demonstrated by live cell imaging and quantification of aggregates. However, the kalirin-7-mediated synphilin-1 aggresome response was not dependent on the GEF activity of kalirin-7 since various dominant negative small GTPases could not inhibit the formation of aggresomes. Interestingly, the aggresome response was blocked by HDAC6 catalytic mutants and the HDAC inhibitor trichostatin A (TSA). Moreover, kalirin-7 decreased the level of acetylated α-tubulin in response to TSA, which suggests an effect of kalirin-7 on HDAC6-mediated protein transportation and aggresome formation. In summary, this is the first report demonstrating that kalirin-7 leads to the recruitment of synphilin-1 into aggresomes in a HDAC6-dependent manner and also links kalirin-7 to microtubule dynamics.
Mesh Terms:
Acetylation, Animals, Carrier Proteins, Cell Line, Guanine Nucleotide Exchange Factors, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Mice, Microtubules, Mutation, Nerve Tissue Proteins, Protein Binding, Protein Interaction Domains and Motifs, Protein Transport, Protein-Serine-Threonine Kinases, Proteolysis, Signal Transduction
Acetylation, Animals, Carrier Proteins, Cell Line, Guanine Nucleotide Exchange Factors, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Mice, Microtubules, Mutation, Nerve Tissue Proteins, Protein Binding, Protein Interaction Domains and Motifs, Protein Transport, Protein-Serine-Threonine Kinases, Proteolysis, Signal Transduction
PLoS ONE
Date: Jan. 04, 2013
PubMed ID: 23284848
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