Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome

Activity-dependent changes in neuronal function require coordinated regulation of the protein synthesis and protein degradation machinery to maintain protein homeostasis, critical for proper neuronal function. However, the biochemical evidence for this balance and coordination is largely lacking. Leveraging our recent discovery of a neuronal-specific 20S membrane proteasome complex (NMP), we began exploring how neuronal activity regulates its function. Here, we found that the NMP degrades exclusively a large fraction of ribosome-associated nascent polypeptides that are being newly synthesized during neuronal stimulation. Using deep-coverage and global mass spectrometry, we identified the nascent protein substrates of the NMP, which included products encoding immediate-early genes, such as c-Fos and Npas4. Intriguingly, we found that turnover of nascent polypeptides and not full-length proteins through the NMP occurred independent of canonical ubiquitylation pathways. We propose that these findings generally define a neuronal activity-induced protein homeostasis program of coordinated protein synthesis and degradation through the NMP. [Display omitted] •Neuronal membrane proteasomes (NMPs) are regulated by neuronal activity•NMPs degrade ribosome-associated nascent polypeptides during protein synthesis•Substrates of the NMP include immediate early gene products Npas4, Fos, and Arc•Degradation through the NMP does not require ubiquitylation Ramachandran et al. reveal that neuronal activity coordinates degradation of ribosome-associated nascent polypeptides through neuronal plasma membrane proteasomes in a process not requiring the canonical ubiquitylation pathways.