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Mol Cell. 2014 Apr 10;54(1):17-29. doi: 10.1016/j.molcel.2014.02.018. Epub 2014 Mar 20.

Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes.

Author information

1
Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, and Cancer Research Lab, University of California, Berkeley, Berkeley, CA 94720, USA.
2
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
4
Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, and Cancer Research Lab, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: rvance@berkeley.edu.

Abstract

NLR (nucleotide-binding domain [NBD]- and leucine-rich repeat [LRR]-containing) proteins mediate innate immune sensing of pathogens in mammals and plants. How NLRs detect their cognate stimuli remains poorly understood. Here, we analyzed ligand recognition by NLR apoptosis inhibitory protein (NAIP) inflammasomes. Mice express multiple highly related NAIP paralogs that recognize distinct bacterial proteins. We analyzed a panel of 43 chimeric NAIPs, allowing us to map the NAIP domain responsible for specific ligand detection. Surprisingly, ligand specificity was mediated not by the LRR domain, but by an internal region encompassing several NBD-associated α-helical domains. Interestingly, we find that the ligand specificity domain has evolved under positive selection in both rodents and primates. We further show that ligand binding is required for the subsequent co-oligomerization of NAIPs with the downstream signaling adaptor NLR family, CARD-containing 4 (NLRC4). These data provide a molecular basis for how NLRs detect ligands and assemble into inflammasomes.

PMID:
24657167
PMCID:
PMC3988258
DOI:
10.1016/j.molcel.2014.02.018
[Indexed for MEDLINE]
Free PMC Article

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