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Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon–mediated immunity

Nature Immunology volume 12, pages 733–741 (2011)Cite this article

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Abstract

Toll-like receptors (TLRs) shape innate and adaptive immunity to microorganisms. The enzyme IRAK1 transduces signals from TLRs, but mechanisms for its activation and regulation remain unknown. We found here that TLR7 and TLR9 activated the isomerase Pin1, which then bound to IRAK1; this resulted in activation of IRAK1 and facilitated its release from the receptor complex to activate the transcription factor IRF7 and induce type I interferons. Consequently, Pin1-deficient cells and mice failed to mount TLR-mediated, interferon-dependent innate and adaptive immune responses. Given the critical role of aberrant activation of IRAK1 and type I interferons in various immune diseases, controlling IRAK1 activation via inhibition of Pin1 may represent a useful therapeutic approach.

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Figure 1: Pin1 is activated and required for cytokine and especially type I interferon secretion after TLR stimulation.
Figure 2: Identification of IRAK1 as a major Pin1 substrate after TLR stimulation, by a proteomics approach.
Figure 3: Phosphorylated Ser131-Pro132, S144-Pro145 and S173-Pro174 sites in the IRAK1 undetermined domain bind to and are isomerized by Pin1.
Figure 4: Pin1 is essential for IRAK1 activation after TLR ligation.
Figure 5: Pin1 facilitates IRAK1 release from the receptor complex to activate IRF7 after TLR ligation.
Figure 6: Pin1 is required for IRF7 activation and IFN-α production after TLR ligation in vitro.
Figure 7: Pin1 is required for TLR-mediated, type I interferon-dependent innate and adaptive immunity in vivo.

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Acknowledgements

We thank L. Cantley, T. Hunter, H. Wu and S. Lin for advice and critical reading of the manuscript; L. Brossay (Brown University) and J.D. Hamilton (Duke University Medical Center) for MCMV-GFP; R. Welsh (University of Massachusetts) for H1N1 virus; and S. Whelan (Harvard Medical School) for VSV-GFP. Supported by the Swiss Foundation for Grants in Biology and Medicine (A.T.K.), the US National Institutes of Health (AG029385 to L.K.N. and K.P.L.; DK066917 to M.A.E.; and GM058556), the American Asthma Foundation (K.P.L.) and the Alliance for Lupus Research (K.P.L.).

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  1. Adrian Tun-Kyi and Greg Finn: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Adrian Tun-Kyi, Greg Finn, Michael Nowak, Tae Ho Lee, John M Asara, George C Tsokos, Mark Exley & Kun Ping Lu

  2. Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA

    Alex Greenwood & Linda K Nicholson

  3. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Kate Fitzgerald

  4. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Elliot Israel

  5. Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Xiaoxia Li

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Contributions

A.T.K. and G.F. designed and did the experiments and wrote the manuscript; A.G. did nuclear magnetic resonance experiments; M.N. and T.H.L. provided technical assistance; J.M.A. did mass spectrometry analysis; K.F., X.L., G.C.T., M.E. and E.I. provided reagents and technical expertise; and L.K.N. and K.P.L. designed the experiments, supervised the project and wrote the manuscript.

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Correspondence to Kun Ping Lu.

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Tun-Kyi, A., Finn, G., Greenwood, A. et al. Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon–mediated immunity. Nat Immunol 12, 733–741 (2011). https://doi.org/10.1038/ni.2069

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