Authors
Ainatzi S, Kaufmann SV, Silbern I, Georgiev SV, Lorenz S, Rizzoli SO, Urlaub H
Journal
Molecular & Cellular Proteomics
Citation
Mol Cell Proteomics. 2025 Mar 13:100946.
Abstract
Neuronal communication relies on neurotransmitter release from synaptic vesicles (SVs), whose dynamics are controlled by Ca2+-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 Ca2+ influx, with the most pronounced changes in CaMKIIα and the clathrin adaptor protein AP180. To validate this finding, we generated a CaMKIIα mutant lacking the ubiquitination target site (K291) and analysed it both in neurons and non-neuronal cells. K291 ubiquitination, close to an important site for CaMKIIα autophosphorylation (T286), influences the synaptic function of this kinase. We suggest that ubiquitination in response to synaptic activity is an important regulator of synaptic function.
