Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction

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Abstract
SUMOylation is a reversible covalent post-translational modification that involves the conjugation of a member of the small ubiquitin-like modifier (SUMO) family to lysine residues in target proteins. SUMO proteins are conjugated by an enzymatic pathway and can mediate a diverse range of subsequent fates for substrate proteins. In a number of systems, both covalent attachment of SUMO and non-covalent binding to SUMO contribute to functional outcomes. Recently, a number of SUMO interacting motifs (SIMs) have been reported that allow proteins to bind to SUMO. SUMOylation is best characterized in the nucleus; however, numerous extranuclear substrates have also been reported. Potential roles for extranuclear SUMOylation include the regulation of G-protein, kinase and phosphatase signalling, axonal mRNA trafficking, and mitochondrial fission and apoptosis. At the plasma membrane, SUMOylation has been implicated in the regulation of a number of key proteins, including glucose transporters, potassium channels and glutamate receptors. SUMOylation has a central role in synapse formation through the modification of the transcription factor MEF2A. Active MEF2A inhibits synapse formation, and the activity-dependent interplay between SUMOylation, phosphorylation and acetylation of MEF2A can suppress this inhibition. A role for SUMO in various neurological disorders is becoming increasingly well documented. Numerous forms of neuronal inclusions stain positive for SUMO family members, and proteins involved in the pathogenesis of disorders such as Huntington's disease, Parkinson's disease and Alzheimer's disease have been reported to be SUMO substrates. SUMO features in various cellular stress responses. For example, large changes in protein SUMOylation have been reported upon cellular oxidative stress and ischemia.