UNC-18 promotes both the anterograde trafficking and synaptic function of syntaxin

The SM protein UNC-18 has been proposed to regulate several aspects of secretion, including synaptic vesicle docking, priming, and fusion. Here, we show that UNC-18 has a chaperone function in neurons, promoting anterograde transport of the plasma membrane soluble N-ethylmaleimide-sensitive factor a...

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Bibliographic Details
Published in:Molecular biology of the cell 2008-09, Vol.19 (9), p.3836-3846
Main Authors: McEwen, Jason M, Kaplan, Joshua M
Format: Article
Language:English
Subjects:
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins - metabolism
Endoplasmic Reticulum - metabolism
Gene Expression Regulation
Glycoside Hydrolases - metabolism
Green Fluorescent Proteins - metabolism
Models, Biological
Mutation
Neurons - metabolism
Phosphoproteins - metabolism
Protein Structure, Tertiary
Protein Transport
Qa-SNARE Proteins - metabolism
Synapses - metabolism
Vesicular Transport Proteins - metabolism
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Summary:The SM protein UNC-18 has been proposed to regulate several aspects of secretion, including synaptic vesicle docking, priming, and fusion. Here, we show that UNC-18 has a chaperone function in neurons, promoting anterograde transport of the plasma membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein Syntaxin-1. In unc-18 mutants, UNC-64 (Caenorhabditis elegans Syntaxin-1) accumulates in neuronal cell bodies. Colocalization studies and analysis of carbohydrate modifications both suggest that this accumulation occurs in the endoplasmic reticulum. This trafficking defect is specific for UNC-64 Syntaxin-1, because 14 other SNARE proteins and two active zone markers were unaffected. UNC-18 binds to Syntaxin through at least two mechanisms: binding to closed Syntaxin, or to the N terminus of Syntaxin. It is unclear which of these binding modes mediates UNC-18 function in neurons. The chaperone function of UNC-18 was eliminated in double mutants predicted to disrupt both modes of Syntaxin binding, but it was unaffected in single mutants. By contrast, mutations predicted to disrupt UNC-18 binding to the N terminus of Syntaxin caused significant defects in locomotion behavior and responsiveness to cholinesterase inhibitors. Collectively, these results demonstrate the UNC-18 acts as a molecular chaperone for Syntaxin transport in neurons and that the two modes of UNC-18 binding to Syntaxin are involved in different aspects of UNC-18 function.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.e08-02-0160