Broad detection of bacterial type III secretion system and flagellin proteins by the human NAIP/NLRC4 inflammasome.

Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE

Original Publication: Washington, DC : National Academy of Sciences

CARD Signaling Adaptor Proteins/*metabolism ; Calcium-Binding Proteins/*metabolism ; Flagellin/*metabolism ; Inflammasomes/*metabolism ; Neuronal Apoptosis-Inhibitory Protein/*metabolism ; Type III Secretion Systems/*metabolism; Animals ; Cells, Cultured ; Humans ; Immunity, Innate ; Mice ; Salmonella typhimurium/immunology

Inflammasomes are cytosolic multiprotein complexes that initiate host defense against bacterial pathogens by activating caspase-1-dependent cytokine secretion and cell death. In mice, specific nucleotide-binding domain, leucine-rich repeat-containing family, apoptosis inhibitory proteins (NAIPs) activate the nucleotide-binding domain, leucine-rich repeat-containing family, CARD domain-containing protein 4 (NLRC4) inflammasome upon sensing components of the type III secretion system (T3SS) and flagellar apparatus. NAIP1 recognizes the T3SS needle protein, NAIP2 recognizes the T3SS inner rod protein, and NAIP5 and NAIP6 recognize flagellin. In contrast, humans encode a single functional NAIP, raising the question of whether human NAIP senses one or multiple bacterial ligands. Previous studies found that human NAIP detects both flagellin and the T3SS needle protein and suggested that the ability to detect both ligands was achieved by multiple isoforms encoded by the single human NAIP gene. Here, we show that human NAIP also senses the Salmonella Typhimurium T3SS inner rod protein PrgJ and that T3SS inner rod proteins from multiple bacterial species are also detected. Furthermore, we show that a single human NAIP isoform is capable of sensing the T3SS inner rod, needle, and flagellin. Our findings indicate that, in contrast to murine NAIPs, promiscuous recognition of multiple bacterial ligands is conferred by a single human NAIP.
Competing Interests: The authors declare no conflict of interest.

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R25 GM071745 United States GM NIGMS NIH HHS; T32 GM007229 United States GM NIGMS NIH HHS; R01 AI123243 United States AI NIAID NIH HHS; P30 CA016520 United States CA NCI NIH HHS; R01 AI118861 United States AI NIAID NIH HHS; United Kingdom Wellcome Trust; R01 CA188034 United States CA NCI NIH HHS

Keywords: NAIP; NLRC4; flagellin; inflammasome; type III secretion system

0 (CARD Signaling Adaptor Proteins)
0 (Calcium-Binding Proteins)
0 (Inflammasomes)
0 (NAIP protein, human)
0 (NLRC4 protein, human)
0 (Neuronal Apoptosis-Inhibitory Protein)
0 (Type III Secretion Systems)
12777-81-0 (Flagellin)

Date Created: 20171129 Date Completed: 20180705 Latest Revision: 20181113

20240829

PMC5740664

10.1073/pnas.1710433114

29180436