Alternative titles; symbols
HGNC Approved Gene Symbol: NEK7
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38) : 1:198,156,998-198,322,420 (from NCBI)
NIMA-related kinases share high amino acid sequence identity with the gene product of the Aspergillus nidulans 'never in mitosis A' gene, which controls initiation of mitosis (summary by Kimura and Okano, 2001).
By EST database analysis with the NIMA sequence as query, Kimura and Okano (2001) identified human NEK7. The deduced 302-amino acid protein has a predicted molecular mass of 34.5 kD. It contains 12 conserved regions characteristic of protein kinase catalytic domains, including a DIKPAN motif that suggests serine/threonine kinase activity. Human NEK7 shares 97%, 77%, 77%, and 64% sequence identity with mouse Nek7, human NEK6 (604884), mouse Nek6, and C. elegans F19H6.1, respectively. By RT-PCR, Kimura and Okano (2001) found highest expression of NEK7 in lung, muscle, testis, brain, heart, liver, leukocyte, and spleen. Faint bands were detected in ovary, prostate, and kidney, and no transcript was amplified from small intestine.
He et al. (2016) reported the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3 (606416)-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 (147678) activation and IL1-beta (147720) release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 (604578) inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC (PYCARD; 606838) oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the cryopyrin-associated periodic fever syndromes (CAPS; see 120100)-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimeras reconstituted with wildtype, Nek7 -/-, or Nlrp3 -/- hematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. The authors concluded that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.
Cryoelectron Microscopy
Sharif et al. (2019) reported a cryoelectron microscopy structure of inactive human NLRP3 (606416) in complex with NEK7 at a resolution of 3.8 angstroms. 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 was confirmed by mutagenesis both in vitro and in cells. Modeling of an active NLRP3-NEK7 conformation based on the NLRC4 (606831) inflammasome predicted an additional contact between an NLRP3-bound NEK7 and a neighboring NLRP3. Mutations to this interface abolished the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. Sharif et al. (2019) concluded that their data suggested that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.
By somatic cell hybrid and radiation hybrid analysis, Kimura and Okano (2001) mapped the NEK7 gene to chromosome 1q31.3.
He, Y., Zeng, M. Y., Yang, D., Motro, B., Nunez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530: 354-357, 2016. [PubMed: 26814970] [Full Text: https://doi.org/10.1038/nature16959]
Kimura, M., Okano, Y. Identification and assignment of the human NIMA-related protein kinase 7 gene (NEK7) to human chromosome 1q31.3. Cytogenet. Cell Genet. 94: 33-38, 2001. [PubMed: 11701951] [Full Text: https://doi.org/10.1159/000048779]
Sharif, H., Wang, L., Wang, W. L., Magupalli, V. G., Andreeva, L., Qiao, Q., Hauenstein, A. V., Wu, Z., Nunez, G., Mao, Y., Wu, H. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature 570: 338-343, 2019. [PubMed: 31189953] [Full Text: https://doi.org/10.1038/s41586-019-1295-z]