Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome PMID: 31189953

ADC Targets in Oncology

2026-04-10

Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome

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

Humayun Sharif ^# ¹ ² , Li Wang ^# ¹ ² , Wei Li Wang ^# ¹ ² ³ ⁴ ⁵ ⁶ ⁷ , Venkat Giri Magupalli ¹ ² , Liudmila Andreeva ¹ ² , Qi Qiao ¹ ² , Arthur V Hauenstein ¹ ² , Zhaolong Wu ³ ⁴ , Gabriel Núñez ⁸ , Youdong Mao ⁹ ¹⁰ ¹¹ ¹² ¹³ , Hao Wu ¹⁴ ¹⁵

Affiliations

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. [email protected].
10. Center for Quantitative Biology, Peking University, Beijing, China. [email protected].
11. Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
12. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
13. Department of Microbiology, Harvard Medical School, Boston, MA, USA. [email protected].
14. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
15. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. [email protected].
# Contributed equally.

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.