Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes

Mol Cell. 2014 Apr 10;54(1):17-29. doi: 10.1016/j.molcel.2014.02.018. Epub 2014 Mar 20.


NLR (nucleotide-binding domain [NBD]- and leucine-rich repeat [LRR]-containing) proteins mediate innate immune sensing of pathogens in mammals and plants. How NLRs detect their cognate stimuli remains poorly understood. Here, we analyzed ligand recognition by NLR apoptosis inhibitory protein (NAIP) inflammasomes. Mice express multiple highly related NAIP paralogs that recognize distinct bacterial proteins. We analyzed a panel of 43 chimeric NAIPs, allowing us to map the NAIP domain responsible for specific ligand detection. Surprisingly, ligand specificity was mediated not by the LRR domain, but by an internal region encompassing several NBD-associated α-helical domains. Interestingly, we find that the ligand specificity domain has evolved under positive selection in both rodents and primates. We further show that ligand binding is required for the subsequent co-oligomerization of NAIPs with the downstream signaling adaptor NLR family, CARD-containing 4 (NLRC4). These data provide a molecular basis for how NLRs detect ligands and assemble into inflammasomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Evolution, Molecular
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Inflammasomes / genetics
  • Inflammasomes / immunology
  • Inflammasomes / metabolism*
  • Ligands
  • Mice
  • Models, Molecular
  • Neuronal Apoptosis-Inhibitory Protein / genetics
  • Neuronal Apoptosis-Inhibitory Protein / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Protein Structure, Secondary
  • Signal Transduction
  • Transfection


  • Apoptosis Regulatory Proteins
  • Bacterial Proteins
  • Calcium-Binding Proteins
  • Inflammasomes
  • Ipaf protein, mouse
  • Ligands
  • Naip6 protein, rat
  • Neuronal Apoptosis-Inhibitory Protein