title: Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs.
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.
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Yan
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wang
authors.forename: Lijun
authors.initials: L
authors.lastname: Luo
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.forename: Baoxue
authors.initials: B
authors.lastname: Ge
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D044082:Citrobacter rodentium / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D054308:Enteropathogenic Escherichia coli / Q000276:immunology / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D061626:Immunoreceptor Tyrosine-Based Inhibition Motif / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination
chemical_list: D029968:Escherichia coli Proteins; D011956:Receptors, Cell Surface; D048029:TNF Receptor-Associated Factor 6; C109287:Tir protein, E coli; D025801:Ubiquitin; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse