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Mol Cell. 2018 Jul 5;71(1):169-177.e6. doi: 10.1016/j.molcel.2018.06.013.

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

Author information

1
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: kapil_ramachandran@hms.harvard.edu.
2
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
3
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
The Johns Hopkins University School of Medicine Microscope Facility, Baltimore, MD 21205, USA.
6
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: smargol7@jhmi.edu.

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.

KEYWORDS:

immediate early gene; membrane proteasome; nascent polypeptide; neuronal activity; proteasome; ribosome

PMID:
29979964
PMCID:
PMC6070390
[Available on 2019-07-05]
DOI:
10.1016/j.molcel.2018.06.013
[Indexed for MEDLINE]

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