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

• 成果类型: Article
• 署名作者: Sun, Chao; Desch, Kristina; Nassim-Assir, Belquis; Giandomenico, Stefano L.; Nemcova, Paulina; Langer, Julian D.; Schuman, Erin M.
• 署名单位: Max Planck Society; Max Planck Society; Aarhus University; University of Bonn
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11696
• DOI: 10.1126/science.adf2018
• 发表日期: 2023-05-26
• 页码: 811-+
• 关键词: activity-dependent regulation; 26s proteasomes; ampa; degradation; ubiquitin; identification; TRAFFICKING; proteins; intact

摘要

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.