Calcium-triggered (de)ubiquitination events in synapses
Ainatzi, S.; Kaufmann, S. V.; Silbern, I.; Georgiev, S. V.; Lorenz, S.; Rizzoli, S. O.; Urlaub, H.
Show abstract
Neuronal communication relies on neurotransmitter release from synaptic vesicles (SVs), whose dynamics are controlled by calcium-dependent pathways, as many thoroughly studied phosphorylation cascades. However, little is known about other post-translational modifications, as ubiquitination. To address this, we analysed resting and stimulated synaptosomes (isolated synapses) by quantitative mass spectrometry. We identified more than 5,000 ubiquitination sites on [~]2,000 proteins, the majority of which participate in SV recycling processes. Several proteins showed significant changes in ubiquitination in response to calcium influx, with the most pronounced changes in CaMKII and the clathrin adaptor protein AP180. To validate this finding, we generated a CaMKII mutant lacking the ubiquitination target site (K291) and analysed it both in neurons and non-neuronal cells. K291 ubiquitination influences CaMKII activity and synaptic function by modulating its autophosphorylation at a functionally important site (T286). We suggest that ubiquitination in response to synaptic activity is an important regulator of synaptic function.
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