Increased Polyubiquitination and Proteasomal Degradation of a Munc18-1 Disease-Linked Mutant Causes Temperature-Sensitive Defect in Exocytosis

Mutations in Munc18-1, an essential component of the machinery controlling neurotransmission, are linked to the development of early infantile epileptic encephalopathy (EIEE).In this study, Martin et al. show that one of these mutations, C180Y, results in a thermolabile protein with a strong propensity to aggregate.The level of Munc18-1C180Y is regulated by K48-linked polyubiquitination and proteasomal degradation.The impaired exocytic function of Munc18-1C180Y is rescued by growth at a permissive temperature.An imbalance in exocytosis could therefore underpin EIEE.