Molecular mechanism for NLRP6 inflammasome assembly and activation

Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2052-2057. doi: 10.1073/pnas.1817221116. Epub 2019 Jan 23.


Inflammasomes are large protein complexes that trigger host defense in cells by activating inflammatory caspases for cytokine maturation and pyroptosis. NLRP6 is a sensor protein in the nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing (NLR) inflammasome family that has been shown to play multiple roles in regulating inflammation and host defenses. Despite the significance of the NLRP6 inflammasome, little is known about the molecular mechanism behind its assembly and activation. Here we present cryo-EM and crystal structures of NLRP6 pyrin domain (PYD). We show that NLRP6 PYD alone is able to self-assemble into filamentous structures accompanied by large conformational changes and can recruit the ASC adaptor using PYD-PYD interactions. Using molecular dynamics simulations, we identify the surface that the NLRP6 PYD filament uses to recruit ASC PYD. We further find that full-length NLRP6 assembles in a concentration-dependent manner into wider filaments with a PYD core surrounded by the NBD and the LRR domain. These findings provide a structural understanding of inflammasome assembly by NLRP6 and other members of the NLR family.

Keywords: NLRP6; X-ray crystallography; cryo-EM; inflammasome; innate immunity.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Humans
  • Immunity, Innate
  • Inflammasomes / metabolism*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Protein Conformation
  • Protein Multimerization


  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • NLRP6 protein, human

Associated data

  • PDB/6NCV
  • PDB/6NDJ