Inhibition of TLR Signaling by a Bacterial Protein Containing Immunoreceptor Tyrosine-Based Inhibitory Motifs

Nat Immunol. 2012 Nov;13(11):1063-71. doi: 10.1038/ni.2417. Epub 2012 Sep 23.

Abstract

The protein Tir (translocated intimin receptor) in enteric bacteria shares sequence similarity with the host cellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). Despite the importance of Tir in pedestal formation, relatively little is known about the role of Tir and its ITIMs in the regulation of the host immune response. Here we demonstrate that Tir from enteropathogenic Escherichia coli (EPEC) interacted with the host cellular tyrosine phosphatase SHP-1 in an ITIM phosphorylation-dependent manner. The association of Tir with SHP-1 facilitated the recruitment of SHP-1 to the adaptor TRAF6 and inhibited the ubiquitination of TRAF6. Moreover, the ITIMs of Tir suppressed EPEC-stimulated expression of proinflammatory cytokines and inhibited intestinal immunity to infection with Citrobacter rodentium. Our findings identify a previously unknown mechanism by which bacterial ITIM-containing proteins can inhibit innate immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Citrobacter rodentium / immunology
  • Enterobacteriaceae Infections / genetics
  • Enterobacteriaceae Infections / immunology*
  • Enterobacteriaceae Infections / microbiology
  • Enteropathogenic Escherichia coli / immunology
  • Enteropathogenic Escherichia coli / pathogenicity
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / immunology*
  • Gene Expression Regulation / immunology
  • Host-Pathogen Interactions
  • Immunity, Innate
  • Immunity, Mucosal
  • Immunoreceptor Tyrosine-Based Inhibition Motif / genetics
  • Immunoreceptor Tyrosine-Based Inhibition Motif / immunology*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Intestines / immunology*
  • Intestines / microbiology
  • Macrophages / immunology
  • Macrophages / microbiology
  • Mice
  • Phosphorylation
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology
  • Ubiquitin / genetics
  • Ubiquitin / immunology
  • Ubiquitination

Substances

  • Escherichia coli Proteins
  • Receptors, Cell Surface
  • TNF Receptor-Associated Factor 6
  • Tir protein, E coli
  • Ubiquitin
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse