Structural mechanism for NEK7-licensed NLRP3 inflammasome activation

By H. Sharif, Li Wang, W. L. Wang, V. Magupalli, Liudmila Andreeva, Q. Qiao, Arthur V. Hauenstein, Zhaolong Wu, G. Núñez, Youdong Mao and 1 more. Nature, 2019

645 citations recorded by the source corpus.

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. A cryo-electron microscopy structure of human NLRP3 in complex with the mitotic kinase NEK7 provides insights into the interactions that mediate the activation of the NLRP3 inflammasome.

Subfields: Immunology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/50dde58a3ec83377708b3de829438c13d1f2fe34

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Citations in the corpus

Inflammation and atherosclerosis: signaling pathways and therapeutic intervention (2022, background): “The PYD domain is also required for ASC selfassociation as well as interaction with NLRP3.”
An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “Importantly, the localization of NLRP3 to the MTOC leads to its interaction with the centrosome-localized mitotic kinase NEK7 to facilitate NLRP3 inflammasome assembly.(10) Furthermore, a recent study showed that the dynein adapter histone deacetylase 6 (HDAC6) is critical for microtubule transport,”