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Nat Commun. 2018 Jun 29;9(1):2550. doi: 10.1038/s41467-018-04947-6.

Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity.

Author information

1
Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
2
Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, 230027, China.
3
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
4
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.
5
Hefei National Laboratory for Physical Sciences at Microscale, Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China.
6
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. xmdeng@xmu.edu.cn.
7
Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China. ustcjw@ustc.edu.cn.
8
Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China. zrb1980@ustc.edu.cn.
9
Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, 230027, China. zrb1980@ustc.edu.cn.

Abstract

Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori's anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.

PMID:
29959312
PMCID:
PMC6026158
DOI:
10.1038/s41467-018-04947-6
[Indexed for MEDLINE]
Free PMC Article

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