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Publication Detail
Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Martin S, Papadopulos A, Tomatis VM, Sierecki E, Malintan NT, Gormal RS, Giles N, Johnston WA, Alexandrov K, Gambin Y, Collins BM, Meunier FA
  • Publication date:
    09/10/2014
  • Pagination:
    206, 218
  • Journal:
    Cell Rep
  • Volume:
    9
  • Issue:
    1
  • Status:
    Published
  • Country:
    United States
  • PII:
    S2211-1247(14)00735-9
  • Language:
    eng
  • Keywords:
    Animals, Exocytosis, Humans, Models, Molecular, Munc18 Proteins, Point Mutation, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Secondary, Rats, SNARE Proteins, Ubiquitination
Abstract
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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