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Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs

Nature Immunology volume 13, pages 1063–1071 (2012)Cite this article

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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.

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Figure 1: Interaction of Tir with SHP-1.
Figure 2: ITIM phosphorylation–dependent interaction of Tir with SHP-1.
Figure 3: Tir facilitates the binding of TRAF6 to SHP-1 and prevents ubiquitination of TRAF6.
Figure 4: Specific inhibition of cytokine production by EPEC (JPN15) Tir.
Figure 5: ITIM-dependent inhibition of cytokine production.
Figure 6: Inhibition of cytokine production via SHP-1.
Figure 7: Tir inhibits immune responses to infection with C. rodentium.
Figure 8: Specific inhibition of intestinal immunity by Tir.

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Acknowledgements

We thank J. Leong (University of Massachusetts Medical School) for cDNA encoding Tir and for JPN15 and JPN15ΔTir; R. Longnecker (Northwestern University) for cDNA encoding LMP2A; H. Gu (University of Colorado Denver) for the SHP-1 construct; B. Finlay and W. Deng (University of British Columbia) for C. rodentium, C. rodentiumΔTir, EPEC strain E2348/69 and ΔescN and technical help; X. Song for help with animal infection; and members of the B. Ge laboratory for discussions and technical assistance. Supported by the National Basic Research Program of China (973 Programs 2012CB578100 and 2011CB505000), the National Natural Science Foundation of China (project 31030028) and the Science and Technology Commission of Shanghai Municipality (Program 10JC1416400).

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Authors and Affiliations

  1. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiaotong University School of Medicine, Shanghai, China

    Dapeng Yan, Lijun Luo & Baoxue Ge

  2. Graduate School of Chinese Academy of Sciences, Beijing, China

    Dapeng Yan

  3. Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

    Xingyu Wang & Baoxue Ge

  4. Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China

    Xingyu Wang & Baoxue Ge

  5. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China

    Xuetao Cao

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Contributions

D.Y., X.C. and B.G. designed this study; D.Y. did experiments, assisted by X.W. and L.L.; D.Y. and B.G. analyzed the data and wrote the manuscript; and all authors discussed the results and commented on the manuscript.

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Correspondence to Baoxue Ge.

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Yan, D., Wang, X., Luo, L. et al. Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs. Nat Immunol 13, 1063–1071 (2012). https://doi.org/10.1038/ni.2417

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