Influenza A viruses limit NLRP3-NEK7-complex formation and pyroptosis in human macrophages

EMBO Rep. 2020 Dec 3;21(12):e50421. doi: 10.15252/embr.202050421. Epub 2020 Nov 12.


Pyroptosis is a fulminant form of macrophage cell death, contributing to release of pro-inflammatory cytokines. In humans, it depends on caspase 1/4-activation of gasdermin D and is characterized by the release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1-F2) of contemporary H5N1 and H3N2 influenza A viruses (IAV) curtails fulminant cell death of infected human macrophages. Infection of macrophages with a PB1-F2-deficient mutant of a contemporary IAV resulted in higher levels of caspase-1 activation, cleavage of gasdermin D, and release of LDH and IL-1β. Mechanistically, PB1-F2 limits transition of NLRP3 from its auto-repressed and closed confirmation into its active state. Consequently, interaction of a recently identified licensing kinase NEK7 with NLRP3 is diminished, which is required to initiate inflammasome assembly.

Keywords: NEK7; NLRP3; PB1-F2; influenza A virus; pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Inflammasomes / genetics
  • Influenza A Virus, H3N2 Subtype
  • Influenza A Virus, H5N1 Subtype*
  • Influenza A virus* / genetics
  • Macrophages
  • NIMA-Related Kinases
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • Pyroptosis


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NEK7 protein, human
  • NIMA-Related Kinases