Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination
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 degrad...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56737-6 |
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| author | Jing Gao Yang Liu Chenfang Si Rui Guo Shouqiao Hou Xiaosong Liu Houfang Long Di Liu Daichao Xu Zai-Rong Zhang Cong Liu Bing Shan Christoph W. Turck Kaiwen He Yaoyang Zhang |
| author_facet | Jing Gao Yang Liu Chenfang Si Rui Guo Shouqiao Hou Xiaosong Liu Houfang Long Di Liu Daichao Xu Zai-Rong Zhang Cong Liu Bing Shan Christoph W. Turck Kaiwen He Yaoyang Zhang |
| author_sort | Jing Gao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2ef8077f05864986a86dd1919afa5d1e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2ef8077f05864986a86dd1919afa5d1e2025-02-09T12:45:44ZengNature PortfolioNature Communications2041-17232025-02-0116111710.1038/s41467-025-56737-6Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitinationJing Gao0Yang Liu1Chenfang Si2Rui Guo3Shouqiao Hou4Xiaosong Liu5Houfang Long6Di Liu7Daichao Xu8Zai-Rong Zhang9Cong Liu10Bing Shan11Christoph W. Turck12Kaiwen He13Yaoyang Zhang14Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd.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.https://doi.org/10.1038/s41467-025-56737-6 |
| spellingShingle | Jing Gao Yang Liu Chenfang Si Rui Guo Shouqiao Hou Xiaosong Liu Houfang Long Di Liu Daichao Xu Zai-Rong Zhang Cong Liu Bing Shan Christoph W. Turck Kaiwen He Yaoyang Zhang Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination Nature Communications |
| title | Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination |
| title_full | Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination |
| title_fullStr | Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination |
| title_full_unstemmed | Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination |
| title_short | Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination |
| title_sort | aspirin inhibits proteasomal degradation and promotes α synuclein aggregate clearance through k63 ubiquitination |
| url | https://doi.org/10.1038/s41467-025-56737-6 |
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