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Regulation of mGluR7 trafficking by SUMOylation in neurons

Authors
Choi, Ji-Hee; Park, Ji-Young; Suh, Young Ho
Department
Department of Pharmacology, Ajou University School of Medicine; Chronic Inflammatory Disease Research Center, Ajou Research Institute for Innovative Medicine
Abstract
Protein SUMOylation is a post-translational modification by which Small Ubiquitin-like MOdifier (SUMO) proteins are covalently linked to the lysine residues of target proteins via an enzymatic cascade. It has been reported that SUMOylation of synaptic proteins plays important regulatory roles in synapse formation, axonal mRNA transport, channel activity, and receptor endocytosis. The metabotropic glutamate receptor type 7 (mGluR7), a presynaptic G protein-coupled receptor modulates excitatory neurotransmission and synaptic plasticity by inhibiting neurotransmitter release. mGluR7 at Lys889 has been proposed to be modified by SUMO proteins in vitro assays, and a consensus motif for SUMO conjugation is conserved in the C-terminus of mGluR7. However, a recent study has failed to demonstrate the SUMO conjugation of full-length mGluR7 in mammalian cells and neurons. Here we have explored whether mGluR7 is a target of SUMOylation. Using biochemical approaches coupled with confocal imaging, we find that mGluR7 at Lys889, the sole SUMOylation site on the C-terminus of mGluR7 is a target of SUMO conjugation both by SUMO-1 and SUMO-2/3 in HEK293T cells. The SUMOylation of mGluR7 is prevented by SUMO-specific isopeptidase SENP-1. Furthermore, the SUMOylation of mGluR7 mediated by SUMO-1 and SUMO-2/3 is identified in primary cortical neurons. Of particular interest, treatment of mGluR7 with an agonist, L-AP4 leads to a profound decrease of SUMO-1 conjugation of mGluR7, whereas there is no change of agonist-induced SUMO-2/3 conjugation of mGluR7. In addition, we find that mutation of mGluR7 at Lys889 to Arg markedly increases mGluR7 internalization in hippocampal neurons. Overexpression of SENP-1 leads to increased internalization of mGluR7, whereas SENP-1 Cys603Ser, a catalytic inactive mutant has no effects, suggesting that endocytosis of mGluR7 is enhanced by reduced SUMO conjugation of mGluR7. Furthermore, we find that phosphorylation of mGluR7 Ser862 facilitates the SUMOylation at Lys889 and internalization of mGluR7 by SUMOylation. Taken together, these data support a model in which SUMOylation of mGluR7 at Lys889 is critical for stable surface expression of mGluR7 in neurons.
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