Targets and consequences of protein SUMOylation in neurons

Abstract

The post-translational modification of proteins is critical for the spatial and temporal regulation of signalling cascades. This is especially important in the CNS where the processes affecting differentiation, growth, targeting and communication between neurones are highly complex and very tightly regulated. In recent years it has emerged that modification of proteins by members of the SUMO (small ubiquitin-related modifier) family of proteins play key roles in neuronal function. SUMOylation involves the covalent conjugation of a member of the SUMO family to lysine residues in target proteins. Multiple nuclear and perinuclear SUMOylation targets have been reported to be involved in nuclear organisation and transcriptional regulation. In addition, a growing number of extranuclear SUMO substrates have been identified that can have important acute effects on neuronal function. The SUMOylation of both intra- and extranuclear proteins have been implicated in a diverse array of processes that have far-reaching implications for neuronal function and pathophysiology. Here we review the current understanding of the targets and consequences of protein SUMOylation in the brain and examine its established and potential involvement in a wide range of neurological and neurodegenerative diseases.

Fig. 1

SUMO conjugation. SUMO proteins are produced as immature pre-proteins that are first cleaved C-terminally by the SENP proteins to allow their conjugation to substrate proteins (not shown). SUMO proteins are then ‘activated’ for conjugation by formation of a thioester bond between the C-terminus of SUMO and the active site cysteine of the E1 complex in an ATP-dependent process. SUMO is then passed to the active site cysteine of the sole reported SUMO-specific E2 enzyme, Ubc9. Ubc9, either alone or in conjunction with one of a number of reported E3 enzymes, then conjugates SUMO to the lysine residue in the substrate protein, altering the properties of the substrate. SUMOylation can subsequently be reversed, again by the activity of the SENP enzyme.

Fig. 2

SUMOylation and neuronal function. SUMOylation has been reported to regulate various aspects of neuronal function and morphology. Shown are a number of these processes, along with identified SUMO substrates involved in them. See text for more details. Abbreviations: MEF2A, myocyte enhancer factor 2A; CASK, calcium/calmodulin-dependent serine kinase; CB1, cannabinoid receptor 1; mGluR, metabotropic glutamate receptor; Drp1, dynamin-related protein 1.