Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination

Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-02-07
DOI
https://doi.org/10.1038/s41467-025-56737-6
Citations
14
Primary Topic
Histone Deacetylase Inhibitors Research
Type
article
Field-Weighted Citation Impact
11.28

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination

Kaiwen He, Houfang Long, Yaoyang Zhang, Chenfang Si et al.
14 citations
Nature Communications
Histone Deacetylase Inhibitors Research
11.28
article

Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination

Kaiwen He, Houfang Long, Yaoyang Zhang, Chenfang Si, Daichao Xu, Zai-Rong Zhang, Bing Shan, Christoph W. Turck, Shouqiao Hou, Di Liu, Cong Liu, Yan Liu, Xiaosong Liu, Jing Gao, Rui Guo
article en
14 citations

Abstract

Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.

Nature CommunicationsVol. 16(1)
Kunming Institute of Zoology (CN), Chinese Academy of Sciences (CN), Shanghai Institute of Organic Chemistry (CN), Center for Excellence in Molecular Cell Science (CN), Max Planck Institute of Psychiatry (DE), University of Chinese Academy of Sciences (CN)
Natural Science Foundation of Shanghai, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality
Zero hunger
Openalex Percentile: Top 1%
Histone Deacetylase Inhibitors Research
11.28
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.