Cryo-EM structure of the NLRC4CARD filament provides insights into how symmetric and asymmetric supramolecular structures drive inflammasome assembly

Mariusz Matyszewski, Weili Zheng, Jacob Lueck, Brendan Antiochos, Edward H. Egelman, Jungsan Sohn

Research output: Contribution to journalArticle

Abstract

Inflammasomes are supramolecular signaling platforms integral to innate immune defense against invading pathogens. The NOD-like receptor (NLR) family apoptosis inhibitory protein (NAIP)䡠NLR family caspase-recruiting domain (CARD) domain-containing 4 (NLRC4) inflammasome recognizes intracellular bacteria and induces the polymerization of the caspase-1 protease, which in turn executes maturation of interleukin-1 (IL-1) and pyroptosis. Several high-resolution structures of the fully assembled NAIP䡠NLRC4 complex are available, but these structures do not resolve the architecture of the CARD filament in atomic detail. Here, we present the cryo-EM structure of the filament assembled by the CARD of human NLRC4 (NLRC4CARD) at 3.4 Å resolution. The structure revealed that the helical architecture of the NLRC4CARD filament is essentially identical to that of the downstream filament assembled by the CARD of caspase-1 (casp1CARD), but deviates from the split washer-like assembly of the NAIP䡠NLRC4 oligomer. Our results suggest that architectural complementarity is a major driver for the recognition between upstream and downstream CARD assemblies in inflammasomes. Furthermore, a Monte Carlo simulation of the NLRC4CARD filament assembly rationalized why an (un)decameric NLRC4 oligomer is optimal for assembling the helical base of the NLRC4CARD filament. Together, our results explain how symmetric and asymmetric supramolecular assemblies enable high-fidelity signaling in inflammasomes.

Original languageEnglish (US)
Pages (from-to)20240-20248
Number of pages9
JournalJournal of Biological Chemistry
Volume293
Issue number52
DOIs
StatePublished - Dec 28 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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