Editors' ChoiceImmunology

NEK7 activates NLRP3

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Sci. Signal.  23 Feb 2016:
Vol. 9, Issue 416, pp. ec39
DOI: 10.1126/scisignal.aaf5096

The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3, the adaptor protein ASC, and the protease caspase-1, which produces the active forms of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and stimulates pyroptosis, a form of cell death. In the first step of NLRP3 inflammasome activation, inflammatory stimuli activate the transcription factor nuclear factor κB (NF-κB), which induces expression of cytokine-encoding genes. In the second step, pathogen- or danger-associated signals stimulate assembly of the components of the inflammasome, thereby activating caspase-1. Many of these second-step stimuli lead to the efflux of potassium ions, an effect that can be induced experimentally with the ionophore nigericin. Three studies have identified NEK7, a serine and threonine kinase involved in mitosis, as an essential activator of the NLRP3 inflammasome. He et al. purified proteins that formed complexes with NLRP3 from mouse bone marrow–derived macrophages treated with ATP (a danger signal) and identified NEK7 as an NLRP3-binding partner. NEK7-deficient cells showed reduced caspase-1 activation and IL-1β production in response to NLRP3-activating stimuli but not in response to stimuli that activate other inflammasomes. Binding of NEK7 to NLRP3 depended on potassium efflux. The catalytic domain of NEK7 interacted with NLRP3; however, the catalytic activity of NEK7 was not required for NLRP3 activation. NLRP3 with the activating mutation R258W causes periodic fever syndromes. In cells expressing NLRP3(R258W), caspase-1 activation depended on NEK7. Experiments with chimeric mice reconstituted with NEK7-deficient hematopoietic cells showed that NEK7 was required for activation of the NLRP3 inflammasome in vivo. Shi et al. performed a forward genetic screen of N-ethyl-N-nitrosourea–generated mutant mice and found that macrophages from NEK7-mutant mice had defective IL-1β production in response to both LPS, a bacterial signal that activates NF-κB, and nigericin. NEK7 bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner. Chimeric mice reconstituted with NEK7-deficient bone marrow cells produced less IL-1β after intraperitoneal injection of monosodium urate crystals (an NLRP3 stimulus) than did chimeric mice reconstituted with wild-type bone marrow cells. Relative to wild-type mice, NEK7-deficient mice exhibited reduced IL-1β–dependent inflammatory disease in an experimental model of multiple sclerosis. The NEK7-NLRP3 complex was more abundant in cells in interphase than in mitotic cells, and mitotic cells showed reduced activation of caspase-1. Because of the role of NEK7 in modulating microtubule dynamics during mitosis, these data suggest that NEK7 acts a switch that segregates inflammasome activation from cell division. Last, Schmid-Burgk et al. used the CRISPR/Cas9 system in a mouse macrophage cell line to show that knockout of NEK7 rendered cells less sensitive to nigericin-induced pyroptosis. The NEK7-deficient cells had less active caspase-1 and produced less IL-1β in response to nigericin than did NEK7-suffcient cells; however, loss of NEK7 had no effect on the responses of cells to the activation of other inflammasomes. As Van Hauwermeiren and Lamkanfi discuss, these data suggest that diseases associated with the NLRP3-inflammasome might be treated by targeting the NEK7-NLRP3 interaction. However, the mechanism by which NEK7 responds to potassium efflux and whether such a mechanism operates in human macrophages remain to be determined.

H. Shi, Y. Wang, X. Li, X. Zhan, M. Tang, M. Fina, L. Su, D. Pratt, C. H. Bu, S. Hildebrand, S. Lyon, L. Scott, J. Quan, Q. Sun, J. Russell, S. Arnett, P. Jurek, D. Chen, V. V. Kravchenko, J. C. Mathison, E. M. Y. Moresco, N. L. Monson, R. J. Ulevitch, B. Beutler, NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 17, 250–258 (2016). [PubMed]

J. L. Schmid-Burgk, D. Chauhan, T. Schmidt, T. S. Ebert, J. Reinhardt, E. Endl, V. Hornung, A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. J. Biol. Chem. 291, 103–109 (2016). [PubMed]

Y. He, M. Y. Zeng, D. Yang, B. Motro, G. Núñez, NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354–357 (2016). [PubMed]

F. Van Hauwermeiren, M. Lamkanfi, The NEK-sus of the NLRP3 inflammasome. Nat. Immunol. 17, 223–224 (2016). [PubMed]