For my PhD, I joined the laboratory of Pr Jean-Pierre VINCENT in September 1998 (university of Nice, France). I studied the trafficking of two members of the neurotensin (NT) receptor family, the G-protein coupled receptors NTR1 and NTR2. I demonstrated that the phosphorylation of a single tyrosine residue was crucial for the recycling of these receptors. I then functionally characterized the NTR3, a single transmembrane domain receptor also known as sortilin. I demonstrated that this receptor heterodimerized with the NTR1 in human colon cancer cells to modulate the NTR1 signalling. Then I decided to orientate my research towards the field of Neuroscience and made the interesting discovery that the NTR3 was the only NT receptor expressed in human microglial cells. In these cells, the binding of NT to NTR3 activates the MAP and PI3 kinase signalling cascades and the subsequent migration of the activated microglia.
During the Oct 2002 - Nov 2008 period, I worked as a Research Fellow in Pr Jeremy HENLEY's lab in Bristol (UK). My main project was to investigate the trafficking mechanisms of kainate receptors (KARs) in hippocampal neurones. KARs are ionotropic glutamate receptors known to serve central functions in the regulation of neurotransmission and plasticity. During my stay in Bristol, I investigated how synaptic activity and NMDA receptor activation modulate the trafficking of the KAR subunit GluR6. I demonstrated that the surface expression of GluR6 is dynamically regulated by synaptic activity. More recently, we published that GluR6 is sumoylated. Sumoylation is the covalent conjugation of the protein SUMO to specific lysine residues of target proteins. GluR6 is rapidly sumoylated in response to glutamate or kainate. The mutation of the sumoylatable lysine residue into arginine on GluR6 prevents kainate-induced GluR6 internalisation. In agreement with these data, KAR-mediated excitatory postsynaptic currents are decreased by sumoylation and enhanced by desumoylation in electrophysiological recordings of hippocampal slices. These results reveal a previously unsuspected role for the sumoylation process and suggest that it may regulate the functions of other synaptic proteins.
In 2008, I was awarded a Royal Society University Research Fellowship in England and an ATIP-CNRS Fellowship in France to set up my independent research group. I decided to come back to France to work on synaptic sumoylation. The current aim of the lab is to investigate the mechanisms that regulate the sumoylation system in the brain. This work will advance our understanding of how neurones regulate the activity-dependent and synapse-specific sumoylation of target proteins. There is increasing evidence that sumoylation can modulate the functional properties of many synaptic proteins. Interestingly, among these identified sumoylation substrates are several proteins directly implicated in neurological disorders.
Prizes and Awards
SUMOylation is a covalent and reversible enzymatic process that involves the conjugation of a small protein called SUMO (Small Ubiquitin like Modifier) to specific lysine residues of target proteins. Until recently, SUMOylation was thought to target mainly nuclear proteins where it is an essential regulator of their nuclear function. However, we reported that multiple synaptic proteins are substrates for SUMOylation enzymes in neurones (Martin et al., 2007a, Nature).
This raises the possibility that SUMOylation, like other post-translational modifications (such as phosphorylation or ubiquitination), may play important roles in synaptic transmission and brain function. Indeed, we discovered that SUMOylation occurs at the plasma membrane and acts as a trigger for agonist-induced endocytosis of kainate receptors, resulting in the modulation of synaptic transmission in the hippocampus. There is now increasing evidence that SUMOylation can modulate the functional properties of a wide range of proteins in neurones in a number of different ways. However the mechanisms by which the SUMOylation process is regulated in the brain are far from being elucidated.
Intriguingly, among identified neuronal SUMOylation substrates are several proteins directly implicated in neurological disorders. However, despite the recent advances demonstrating the importance of SUMOylation in the brain, little is known about the activity-dependent properties and processes controlling the SUMOylation machinery in neurones.
To address these issues we investigate the processes that regulate the SUMOylation machinery in neurons and we functionally characterize novel synaptic SUMO substrates using molecular, biochemical and live-imaging techniques.
These data will advance our understanding of how neurones regulate the activity-dependent and synapse-specific SUMOylation of target proteins. In addition, the information gained will provide a basis for further studies on the role of SUMOylation in animal models of diseases characterised by synaptic dysfunction. In the longer term, these data will inform on strategies that may provide tractable targets for therapeutic intervention.