Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization

Science. 2015 Oct 23;350(6259):404-9. doi: 10.1126/science.aac5789. Epub 2015 Oct 8.


The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at subnanometer resolution revealed a ~90° hinge rotation accompanying NLRC4 activation. Unlike in the related heptameric Apaf-1 apoptosome, in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP-NLRC4 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

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / chemistry*
  • Bacterial Proteins / chemistry*
  • CARD Signaling Adaptor Proteins / chemistry
  • Calcium-Binding Proteins / chemistry*
  • Caspase 1 / chemistry
  • Cryoelectron Microscopy
  • Immunity, Innate*
  • Inflammasomes / immunology*
  • Mice
  • Molecular Sequence Data
  • Neuronal Apoptosis-Inhibitory Protein / chemistry*
  • Polymerization
  • Protein Interaction Maps
  • Protein Structure, Tertiary


  • Apoptosis Regulatory Proteins
  • Bacterial Proteins
  • CARD Signaling Adaptor Proteins
  • Calcium-Binding Proteins
  • Inflammasomes
  • Ipaf protein, mouse
  • Naip2 protein, mouse
  • Neuronal Apoptosis-Inhibitory Protein
  • Caspase 1

Associated data

  • PDB/3JBL