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

  1. Sunny Shina,1
  1. aDepartment of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
  2. bDepartment of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53706
  1. Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved November 6, 2017 (received for review June 14, 2017)

Significance

Inflammasomes are cytosolic multiprotein complexes that initiate innate immune responses to microbial infection. Inflammasome specificity is determined by cytosolic innate immune sensors, including nucleotide-binding domain, leucine-rich repeat-containing family, apoptosis inhibitory proteins (NAIPs). In mice, which encode seven different NAIPs, individual NAIPs recognize specific components of the structurally related bacterial type III secretion system (T3SS) and flagellar apparatus. Humans encode a single functional NAIP, raising the question of whether human NAIP recognizes the same repertoire of bacterial ligands. Here, we find that, in contrast to the ligand specificity exhibited by the murine NAIPs, the single human NAIP broadly detects multiple T3SS and flagellin proteins. These findings provide a basis for understanding the mechanisms underlying human-specific innate immune responses against bacterial infection.

Abstract

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.

Footnotes

  • ?1To whom correspondence should be addressed. Email: sunshin{at}pennmedicine.upenn.edu.
  • Author contributions: V.M.R.R., J.R., N.N., N.M.P., I.J.S., B.M.Y., M.A.B., and S.S. designed research; V.M.R.R., J.R., N.N., N.M.P., I.J.S., B.M.Y., and M.A.B. performed research; V.M.R.R., J.R., N.N., B.M.Y., M.A.B., D.A.P., and J.-D.S. contributed new reagents/analytic tools; V.M.R.R., J.R., N.N., N.M.P., I.J.S., B.M.Y., M.A.B., and S.S. analyzed data; and V.M.R.R., J.R., N.N., and S.S. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1710433114/-/DCSupplemental.

Published under the PNAS license.

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