BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination
Abstract The ATPase activity of NLRP3 has pivotal role in inflammasome activation and is recognized as a good target for the development of the NLRP3 inflammasome-specific inhibitor. However, signals in the vicinity of the ATPase activity of NLRP3 have not been fully elucidated. Here, we demonstrate...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-15314-8 |
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| author | Do-Wan Shim Woo-Young Shin Sang-Hyeun Yu Byung-Hak Kim Sang-Kyu Ye Sushruta Koppula Hyung-Sik Won Tae-Bong Kang Kwang-Ho Lee |
| author_facet | Do-Wan Shim Woo-Young Shin Sang-Hyeun Yu Byung-Hak Kim Sang-Kyu Ye Sushruta Koppula Hyung-Sik Won Tae-Bong Kang Kwang-Ho Lee |
| author_sort | Do-Wan Shim |
| collection | DOAJ |
| description | Abstract The ATPase activity of NLRP3 has pivotal role in inflammasome activation and is recognized as a good target for the development of the NLRP3 inflammasome-specific inhibitor. However, signals in the vicinity of the ATPase activity of NLRP3 have not been fully elucidated. Here, we demonstrate NLRP3 inflammasome-specific action of a benzoxathiole derivative, BOT-4-one. BOT-4-one exhibited an inhibition of NLRP3 inflammasome activation, which was attributable to its alkylating capability to NLRP3. In particular, the NLRP3 alkylation by BOT-4-one led to an impaired ATPase activity of NLRP3, thereby obstructing the assembly of the NLRP3 inflammasome. Additionally, we found that NLRP3 alkylators, including BOT-4-one, enhance the ubiquitination level of NLRP3, which might also contribute to the inhibition of NLRP3 inflammasome activation. Finally, BOT-4-one appeared to be superior to other known NLRP3 alkylators in inhibiting the functionality of the NLRP3 inflammasome and its resulting anti-inflammatory activity was confirmed in vivo using a monosodium urate-induced peritonitis mouse model. Collectively, the results suggest that NLRP3 alkylators function by inhibiting ATPase activity and increasing the ubiquitination level of NLRP3, and BOT-4-one could be the type of NLRP3 inhibitor that may be potentially useful for the novel development of a therapeutic agent in controlling NLRP3 inflammasome-related diseases. |
| first_indexed | 2024-12-13T16:37:53Z |
| format | Article |
| id | doaj.art-0a6d6584786a45199112246a77ce092a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T16:37:53Z |
| publishDate | 2017-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0a6d6584786a45199112246a77ce092a2022-12-21T23:38:20ZengNature PortfolioScientific Reports2045-23222017-11-017111210.1038/s41598-017-15314-8BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitinationDo-Wan Shim0Woo-Young Shin1Sang-Hyeun Yu2Byung-Hak Kim3Sang-Kyu Ye4Sushruta Koppula5Hyung-Sik Won6Tae-Bong Kang7Kwang-Ho Lee8Department of Applied Life Science, Graduate School, Konkuk UniversityDepartment of Applied Life Science, Graduate School, Konkuk UniversityDepartment of Applied Life Science, Graduate School, Konkuk UniversityDepartment of Pharmacology, Seoul National University College of MedicineDepartment of Pharmacology, Seoul National University College of MedicineDepartment of Biotechnology, Research Institute of Inflammatory Disease, Konkuk UniversityDepartment of Applied Life Science, Graduate School, Konkuk UniversityDepartment of Applied Life Science, Graduate School, Konkuk UniversityDepartment of Applied Life Science, Graduate School, Konkuk UniversityAbstract The ATPase activity of NLRP3 has pivotal role in inflammasome activation and is recognized as a good target for the development of the NLRP3 inflammasome-specific inhibitor. However, signals in the vicinity of the ATPase activity of NLRP3 have not been fully elucidated. Here, we demonstrate NLRP3 inflammasome-specific action of a benzoxathiole derivative, BOT-4-one. BOT-4-one exhibited an inhibition of NLRP3 inflammasome activation, which was attributable to its alkylating capability to NLRP3. In particular, the NLRP3 alkylation by BOT-4-one led to an impaired ATPase activity of NLRP3, thereby obstructing the assembly of the NLRP3 inflammasome. Additionally, we found that NLRP3 alkylators, including BOT-4-one, enhance the ubiquitination level of NLRP3, which might also contribute to the inhibition of NLRP3 inflammasome activation. Finally, BOT-4-one appeared to be superior to other known NLRP3 alkylators in inhibiting the functionality of the NLRP3 inflammasome and its resulting anti-inflammatory activity was confirmed in vivo using a monosodium urate-induced peritonitis mouse model. Collectively, the results suggest that NLRP3 alkylators function by inhibiting ATPase activity and increasing the ubiquitination level of NLRP3, and BOT-4-one could be the type of NLRP3 inhibitor that may be potentially useful for the novel development of a therapeutic agent in controlling NLRP3 inflammasome-related diseases.https://doi.org/10.1038/s41598-017-15314-8 |
| spellingShingle | Do-Wan Shim Woo-Young Shin Sang-Hyeun Yu Byung-Hak Kim Sang-Kyu Ye Sushruta Koppula Hyung-Sik Won Tae-Bong Kang Kwang-Ho Lee BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination Scientific Reports |
| title | BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination |
| title_full | BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination |
| title_fullStr | BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination |
| title_full_unstemmed | BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination |
| title_short | BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination |
| title_sort | bot 4 one attenuates nlrp3 inflammasome activation nlrp3 alkylation leading to the regulation of its atpase activity and ubiquitination |
| url | https://doi.org/10.1038/s41598-017-15314-8 |
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