Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome

Humayun Sharif, Li Wang, Wei Li Wang, Venkat Giri Magupalli, Liudmila Andreeva, Qi Qiao, Arthur V. Hauenstein, Zhaolong Wu, Gabriel Núñez, Youdong Mao () and Hao Wu ()
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Humayun Sharif: Harvard Medical School
Li Wang: Harvard Medical School
Wei Li Wang: Harvard Medical School
Venkat Giri Magupalli: Harvard Medical School
Liudmila Andreeva: Harvard Medical School
Qi Qiao: Harvard Medical School
Arthur V. Hauenstein: Harvard Medical School
Zhaolong Wu: Peking University
Gabriel Núñez: University of Michigan Medical School
Youdong Mao: Peking University
Hao Wu: Harvard Medical School

Nature, 2019, vol. 570, issue 7761, 338-343

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1295-z

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