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Nature. 2019 Jun;570(7761):338-343. doi: 10.1038/s41586-019-1295-z. Epub 2019 Jun 12.

Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome.

Sharif H1,2, Wang L1,2, Wang WL1,2,3,4,5,6,7, Magupalli VG1,2, Andreeva L1,2, Qiao Q1,2, Hauenstein AV1,2, Wu Z3,4, Núñez G8, Mao Y9,10,11,12,13, Wu H14,15.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
2
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
3
State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, China.
4
Center for Quantitative Biology, Peking University, Beijing, China.
5
Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
7
Department of Microbiology, Harvard Medical School, Boston, MA, USA.
8
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
9
State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, China. ymao@pku.edu.cn.
10
Center for Quantitative Biology, Peking University, Beijing, China. ymao@pku.edu.cn.
11
Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA, USA. ymao@pku.edu.cn.
12
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. ymao@pku.edu.cn.
13
Department of Microbiology, Harvard Medical School, Boston, MA, USA. ymao@pku.edu.cn.
14
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. wu@crystal.harvard.edu.
15
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. wu@crystal.harvard.edu.

Abstract

The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-β fibrils and extracellular ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 Å. The earring-shaped NLRP3 consists of curved leucine-rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.

PMID:
31189953
DOI:
10.1038/s41586-019-1295-z

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