A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation

Topic: Brain proteins, microglia and lab models

Inflammasomes are high molecular weight protein complexes that assemble in the cytosol upon pathogen encounter. This results in caspase-1-dependent pro-inflammatory cytokine maturation, as well as a special type of cell death, known as pyroptosis. The Nlrp3 inflammasome plays a pivotal role in pathogen defense, but at the same time, its activity has also been implicated in many common sterile inflammatory conditions. To this effect, several studies have identified Nlrp3 inflammasome engagement in a number of common human diseases such as atherosclerosis, type 2 diabetes, Alzheimer disease, or gout. Although it has been shown that known Nlrp3 stimuli converge on potassium ion efflux upstream of Nlrp3 activation, the exact molecular mechanism of Nlrp3 activation remains elusive. Here, we describe a genome-wide CRISPR/Cas9 screen in immortalized mouse macrophages aiming at the unbiased identification of gene products involved in Nlrp3 inflammasome activation. We employed a FACS-based screen for Nlrp3-dependent cell death, using the ionophoric compound nigericin as a potassium efflux-inducing stimulus. Using a genome-wide guide RNA (gRNA) library, we found that targeting Nek7 rescued macrophages from nigericin-induced lethality. Subsequent studies revealed that murine macrophages deficient in Nek7 displayed a largely blunted Nlrp3 inflammasome response, whereas Aim2-mediated inflammasome activation proved to be fully intact. Although the mechanism of Nek7 functioning upstream of Nlrp3 yet remains elusive, these studies provide a first genetic handle of a component that specifically functions upstream of Nlrp3.

Key findings

• This results in caspase-1-dependent pro-inflammatory cytokine maturation, as well as a special type of cell death, known as pyroptosis.
• Although it has been shown that known Nlrp3 stimuli converge on potassium ion efflux upstream of Nlrp3 activation, the exact molecular mechanism of Nlrp3 activation remains elusive.
• Using a genome-wide guide RNA (gRNA) library, we found that targeting Nek7 rescued macrophages from nigericin-induced lethality.
• Subsequent studies revealed that murine macrophages deficient in Nek7 displayed a largely blunted Nlrp3 inflammasome response, whereas Aim2-mediated inflammasome activation proved to be fully intact.

Why it matters

This laboratory study in mouse cells identified NEK7 as a needed component for activation of the Nlrp3 inflammasome, a process that has been implicated in Alzheimer's disease and other conditions. It is early, cell-based work and does not test any treatment in people.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1074/jbc.c115.700492
• PubMed: 26553871
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• Free full text: PubMed Central →

Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).

@article{schmidburgk2016-26553871,
  author  = {Schmid-Burgk, J. L. and Chauhan, D. and Schmidt, T. and Ebert, T. S. and Reinhardt, J. and Endl, E. and Hornung, V.},
  title   = {{A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation}},
  journal = {The Journal of biological chemistry},
  year    = {2016},
  doi     = {10.1074/jbc.c115.700492},
  pmid    = {26553871},
  url     = {https://doi.org/10.1074/jbc.c115.700492}
}

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