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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0a6d6584786a45199112246a77ce092a
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spelling	oai:doaj.org-article:0a6d6584786a45199112246a77ce092a2021-12-02T15:06:18ZBOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination10.1038/s41598-017-15314-82045-2322https://doaj.org/article/0a6d6584786a45199112246a77ce092a2017-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-15314-8https://doaj.org/toc/2045-2322Abstract 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.Do-Wan ShimWoo-Young ShinSang-Hyeun YuByung-Hak KimSang-Kyu YeSushruta KoppulaHyung-Sik WonTae-Bong KangKwang-Ho LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	bot-4-one attenuates nlrp3 inflammasome activation: nlrp3 alkylation leading to the regulation of its atpase activity and ubiquitination
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0a6d6584786a45199112246a77ce092a
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BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination

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