Synaptic Sumoylation

Abstract

Sumoylation--the posttranslational modification of proteins with the small ubiquitin-like modifier protein (SUMO)--is most familiar in the context of transcriptional regulation and nuclear transport; increasingly, however, roles for extranuclear sumoylation have begun to surface. Martin et al . found that the SUMO-conjugating enzyme Ubc9 and the SUMO ligase PIAS3 interacted with the GluR6 subunit of the kainate type of glutamate receptor (KAR) in a yeast two-hybrid screen of rat brain cDNA and coimmunoprecipitated with GluR6 from cultured hippocampal neuronal extracts. Truncation analysis indicated that interaction depended on a region of GluR6 containing the consensus sumoylation motif. Immunocytochemical analysis indicated that there was limited colocalization of GluR6 and SUMO-1 in cultured hippocampal neurons and that most of the sumoylated GluR6 was intracellular. Kainate, which stimulates KAR internalization and degradation, increased GluR6 sumoylation (as did glutamate), whereas desumoylation with the SUMO-specific isopeptidase SENP-1 inhibited kainate-dependent GluR6 endocytosis. Moreover, unlike fluorescently labeled wild-type GluR6a, a fluorescently labeled non-sumoylatable GluR6a point mutant expressed in COS-7 cells failed to undergo kainate-dependent endocytosis. Infusion of SUMO-1 into CA3 neurons in hippocampal slices decreased the amplitude of KAR-mediated excitatory postsynaptic currents (KAR-EPSCs) without affecting AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor-mediated EPSCs, whereas infusion of SENP-1 increased the amplitude of KAR-EPSCs. Thus, the authors conclude that, under certain conditions, sumoylation may modify the postsynaptic response to glutamate and propose that sumoylation may regulate the function of many other synaptic proteins as well. Coussen and Choquet discuss some of the implications of this research. S. Martin, A. Nishimune, J. R. Mellor, J. M. Henley, SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447 , 321-325 (2007). [PubMed]