Nek7 is an essential mediator of NLRP3 activation downstream of potassium efflux

By Yuan He, M. Zeng, Dahai Yang, B. Motro, G. Núñez. Nature, 2016

1,154 citations recorded by the source corpus.

Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1β and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations. Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli. Despite extensive investigation, the molecular mechanism leading to NLRP3 activation in response to potassium efflux remains unknown. Here we report the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL-1β release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 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 oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the CAPS-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimaeras reconstituted with wild-type, Nek7−/− or Nlrp3−/− haematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. These studies demonstrate that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.

Subfields: Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/470b57aa280ece8079653b1f252bd9473d0b391c

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In Molecular Biology

1. T. Kanneganti
2. G. Núñez
3. Yuan He
4. D. Sharma
5. H. Hara
6. Wei Jiang
7. Yan Yu
8. Weitong Gao

In Nephrology

1. T. Kanneganti
2. G. Núñez

Citations in the corpus

• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “NLRP3 responds to components such as ATP, crystals, and viruses, causing potassium efflux to trigger NLRP3 activity.(120,121) Activated sensor proteins recruit and activate CASP1 via apoptosis-associated speck-like protein containing a CARD (ASC) which together constitute the inflammasome.”
• Mechanism and regulation of NLRP3 inflammasome activation (2016, background): “Furthermore, Nek7 is also required for NLRP3 activation in macrophages harboring a NLRP3-activating mutation (NLRP3) [77].”
• Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders (2017, background): “In addition, NEK7, another component of NLRP3 complex (He et al., 2016; 3225JEM Vol. 214, No. 11 Schmid-Burgk et al., 2016; Shi et al., 2016), was also not pulled down (Fig.”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “The catalytic domain of Nek7, but not its kinase activity, is required for its interaction with the NOD and LRR domains of NLRP3 and inflammasome activation [168,170].”
• Role of pyroptosis in inflammation and cancer (2022, background): “The kinase NEK7, which is responsible for cell spindle formation and centrosome separation, is an on-off regulatory protein that binds to NLRP3 protein and regulates the activation of the NLRP3 inflammasome [81, 82].”
• Inflammation and atherosclerosis: signaling pathways and therapeutic intervention (2022, background): “essential sensor, functions in pathological processes are related to vascular endothelial dysfunction.(364) Thus, targeting NLRP3 may be an effective and potential target for therapeutic intervention in acute and chronic cardiovascular disease.”
• The P2X7 Receptor in Infection and Inflammation (2017, neutral): “In fact, this transcription factor, which is activated by P2X7R in different cell types (Amoroso et al., 2012, 2015; Hirayama et al., 2015), inhibits Treg cell differentiation by promoting proteasomal degradation of Foxp3 (Dang et al.”