Research Article

The structural basis of flagellin detection by NAIP5: A strategy to limit pathogen immune evasion

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Science  17 Nov 2017:
Vol. 358, Issue 6365, pp. 888-893
DOI: 10.1126/science.aao1140

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Another spin at the wheel

The NLR (nucleotide-binding domain leucine-rich repeat) proteins are a key intracellular component of the early innate immune response to pathogens. After binding microbial ligands, assorted NLR family members assemble to form enormous signaling complexes (inflammasomes), which promote pro-inflammatory cytokine secretion and cell death. Tenthorey et al. used cryo-electron microscopy to visualize an assembled ligand-bound inflammasome. They find that when NAIP5 binds flagellin, it changes conformation, which triggers a rotation in monomeric NLRC4, catalyzing further NLRC4 recruitment. Steric clash results in a partially open structure, in contrast with previous descriptions of a closed symmetrical “wheel.” Furthermore, NAIP5 recognizes multiple regions of its ligand, and mutations of flagellin that allow for NAIP5 evasion compromise bacterial fitness.

Science, this issue p. 888


Robust innate immune detection of rapidly evolving pathogens is critical for host defense. Nucleotide-binding domain leucine-rich repeat (NLR) proteins function as cytosolic innate immune sensors in plants and animals. However, the structural basis for ligand-induced NLR activation has so far remained unknown. NAIP5 (NLR family, apoptosis inhibitory protein 5) binds the bacterial protein flagellin and assembles with NLRC4 to form a multiprotein complex called an inflammasome. Here we report the cryo–electron microscopy structure of the assembled ~1.4-megadalton flagellin-NAIP5-NLRC4 inflammasome, revealing how a ligand activates an NLR. Six distinct NAIP5 domains contact multiple conserved regions of flagellin, prying NAIP5 into an open and active conformation. We show that innate immune recognition of multiple ligand surfaces is a generalizable strategy that limits pathogen evolution and immune escape.

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