Mechanism of NAIP—NLRC4 inflammasome activation revealed by cryo-EM structure of unliganded NAIP5

Bhaskar Paidimuddala, Jianhao Cao, Grady Nash, Qing Xie, Hao Wu, Liman Zhang

Research output: Contribution to journalArticlepeer-review


The nucleotide-binding domain (NBD), leucine rich repeat (LRR) domain containing protein family (NLR family) apoptosis inhibitory proteins (NAIPs) are cytosolic receptors that play critical roles in the host defense against bacterial infection. NAIPs interact with conserved bacterial ligands and activate the NLR family caspase recruitment domain containing protein 4 (NLRC4) to initiate the NAIP—NLRC4 inflammasome pathway. Here we found the process of NAIP activation is completely different from NLRC4. Our cryo-EM structure of unliganded mouse NAIP5 adopts an unprecedented wide-open conformation, with the nucleating surface fully exposed and accessible to recruit inactive NLRC4. Upon ligand binding, the winged helix domain (WHD) of NAIP5 undergoes roughly 20° rotation to form a steric clash with the inactive NLRC4, which triggers the conformational change of NLRC4 from inactive to active state. We also show the rotation of WHD places the 17–18 loop at a position that directly bind the active NLRC4 and stabilize the NAIP5–NLRC4 complex. Overall, these data provide structural mechanisms of inactive NAIP5, the process of NAIP5 activation and NAIP-dependent NLRC4 activation.

Original languageEnglish (US)
Pages (from-to)159-166
Number of pages8
JournalNature Structural and Molecular Biology
Issue number2
StatePublished - Feb 2023
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


Dive into the research topics of 'Mechanism of NAIP—NLRC4 inflammasome activation revealed by cryo-EM structure of unliganded NAIP5'. Together they form a unique fingerprint.

Cite this