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

Author:
Ramachandran, Kapil V., Fu, Jack M., Schaffer, Thomas B., Na, Chan Hyun, Delannoy, Michael, Margolis, Seth S.
Source:
Molecular cell 2018 v.71 no.1 pp. 169-177.e6
ISSN:
1097-2765
Subject:
genes, homeostasis, mass spectrometry, neurons, polypeptides, proteasome endopeptidase complex, protein degradation, protein synthesis, proteins
Abstract:
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.