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 af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

34 Citationer (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.

Originalsprog	Engelsk
Artikelnummer	811
Tidsskrift	Science
Vol/bind	380
Nummer	6647
Antal sider	17
ISSN	0036-8075
DOI	https://doi.org/10.1126/SCIENCE.ADF2018
Status	Udgivet - maj 2023

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10.1126/SCIENCE.ADF2018

https://www.biorxiv.org/content/biorxiv/early/2022/10/17/2022.10.17.512557.full.pdfLicens: CC BY-NC-ND

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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.",

author = "Chao Sun and Kristina Desch and Belquis Nassim-Assir and Giandomenico, \{Stefano L.\} and Paulina Nemcova and Langer, \{Julian D.\} and Schuman, \{Erin M.\}",

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AU - Sun, Chao

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

Y1 - 2023/5

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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85160455054

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JO - Science

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

Abstract

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