An abundance of free regulatory (19S) proteasome particles regulates neuronal synapses

Chao Sun; Kristina Desch; Belquis Nassim-Assir; Stefano L. Giandomenico; Paulina Nemcova; Julian D. Langer; Erin M. Schuman

doi:10.1126/SCIENCE.ADF2018

An abundance of free regulatory (19S) proteasome particles regulates neuronal synapses

Chao Sun, Kristina Desch, Belquis Nassim-Assir, Stefano L. Giandomenico, Paulina Nemcova, Julian D. Langer, Erin M. Schuman^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

24 Citations (Scopus)

Abstract

The proteasome, the major protein-degradation machine in cells, regulates neuronal synapses and long-term information storage. Here, using super-resolution microscopy, we found that the two essential subcomplexes of the proteasome, the regulatory (19S) and catalytic (20S) particles, are differentially distributed within individual rat cortical neurons. We discovered an unexpected abundance of free 19S particles near synapses. The free neuronal 19S particles bind and deubiquitylate lysine 63–ubiquitin (Lys⁶³-ub), a non–proteasome-targeting ubiquitin linkage. Pull-down assays revealed a significant overrepresentation of synaptic molecules as Lys⁶³-ub interactors. Inhibition of the 19S deubiquitylase activity significantly altered excitatory synaptic transmission and reduced the synaptic availability of AMPA receptors at multiple trafficking points in a proteasome-independent manner. Together, these results reveal a moonlighting function of the regulatory proteasomal subcomplex near synapses.

Original language	English
Article number	811
Journal	Science
Volume	380
Issue	6647
Number of pages	17
ISSN	0036-8075
DOIs	https://doi.org/10.1126/SCIENCE.ADF2018
Publication status	Published - May 2023

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10.1126/SCIENCE.ADF2018

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title = "An abundance of free regulatory (19S) proteasome particles regulates neuronal synapses",

abstract = "The proteasome, the major protein-degradation machine in cells, regulates neuronal synapses and long-term information storage. Here, using super-resolution microscopy, we found that the two essential subcomplexes of the proteasome, the regulatory (19S) and catalytic (20S) particles, are differentially distributed within individual rat cortical neurons. We discovered an unexpected abundance of free 19S particles near synapses. The free neuronal 19S particles bind and deubiquitylate lysine 63–ubiquitin (Lys63-ub), a non–proteasome-targeting ubiquitin linkage. Pull-down assays revealed a significant overrepresentation of synaptic molecules as Lys63-ub interactors. Inhibition of the 19S deubiquitylase activity significantly altered excitatory synaptic transmission and reduced the synaptic availability of AMPA receptors at multiple trafficking points in a proteasome-independent manner. Together, these results reveal a moonlighting function of the regulatory proteasomal subcomplex near synapses.",

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AU - Desch, Kristina

AU - Nassim-Assir, Belquis

AU - Giandomenico, Stefano L.

AU - Nemcova, Paulina

AU - Langer, Julian D.

AU - Schuman, Erin M.

PY - 2023/5

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N2 - The proteasome, the major protein-degradation machine in cells, regulates neuronal synapses and long-term information storage. Here, using super-resolution microscopy, we found that the two essential subcomplexes of the proteasome, the regulatory (19S) and catalytic (20S) particles, are differentially distributed within individual rat cortical neurons. We discovered an unexpected abundance of free 19S particles near synapses. The free neuronal 19S particles bind and deubiquitylate lysine 63–ubiquitin (Lys63-ub), a non–proteasome-targeting ubiquitin linkage. Pull-down assays revealed a significant overrepresentation of synaptic molecules as Lys63-ub interactors. Inhibition of the 19S deubiquitylase activity significantly altered excitatory synaptic transmission and reduced the synaptic availability of AMPA receptors at multiple trafficking points in a proteasome-independent manner. Together, these results reveal a moonlighting function of the regulatory proteasomal subcomplex near synapses.

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An abundance of free regulatory (19S) proteasome particles regulates neuronal synapses

Abstract

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