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BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination
- Source :
- Scientific Reports, Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
- Publication Year :
- 2017
-
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.
- Subjects :
- 0301 basic medicine
Alkylation
Inflammasomes
THP-1 Cells
Science
Anti-Inflammatory Agents
Article
03 medical and health sciences
Ubiquitin
In vivo
NLR Family, Pyrin Domain-Containing 3 Protein
medicine
Atpase activity
Animals
Humans
THP1 cell line
Cells, Cultured
Adenosine Triphosphatases
Multidisciplinary
biology
integumentary system
Chemistry
Macrophages
Ubiquitination
Inflammasome
Bridged Bicyclo Compounds, Heterocyclic
Cell biology
Mice, Inbred C57BL
030104 developmental biology
biology.protein
Medicine
Female
NLRP3 inflammasome activation
Function (biology)
medicine.drug
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific reports
- Accession number :
- edsair.doi.dedup.....0b20a0538d5e65e02824903369a762b7