Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis
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Description
Summary Munc18-1 is a critical component of the core machinery controlling neuroexocytosis. Recently, mutations in Munc18-1 leading to the development of early infantile epileptic encephalopathy have been discovered. However, which degradative pathway controls Munc18-1 levels and how it impacts on neuroexocytosis in this pathology is unknown. Using neurosecretory cells deficient in Munc18, we show that a disease-linked mutation, C180Y, renders the protein unstable at 37°C. Although the mutated protein retains its function as t-SNARE chaperone, neuroexocytosis is impaired, a defect that can be rescued at a lower permissive temperature. We reveal that Munc18-1 undergoes K48-linked polyubiquitination, which is highly increased by the mutation, leading to proteasomal, but not lysosomal, degradation. Our data demonstrate that functional Munc18-1 levels are controlled through polyubiquitination and proteasomal degradation. The C180Y disease-causing mutation greatly potentiates this degradative pathway, rendering Munc18-1 unable to facilitate neuroexocytosis, a phenotype that is reversed at a permissive temperature.
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ID Code: | 220775 | ||||
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Item Type: | Contribution to Journal (Journal Article) | ||||
Refereed: | Yes | ||||
ORCID iD: |
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Measurements or Duration: | 13 pages | ||||
DOI: | 10.1016/j.celrep.2014.08.059 | ||||
ISSN: | 2211-1247 | ||||
Pure ID: | 32771731 | ||||
Divisions: | Past > Institutes > Institute for Future Environments Current > Research Centres > Centre for Tropical Crops and Biocommodities |
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Copyright Owner: | Consult author(s) regarding copyright matters | ||||
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Deposited On: | 06 Nov 2021 13:31 | ||||
Last Modified: | 26 Jun 2024 21:50 |
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