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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O'Neill, L.A. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol. Rev. 226, 10–18 (2008).
Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).
Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).
Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).
Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196–200 (2002).
Diebold, S.S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).
Heil, F. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).
Liu, Y.J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).
Hoebe, K., Janssen, E. & Beutler, B. The interface between innate and adaptive immunity. Nat. Immunol. 5, 971–974 (2004).
Baccala, R., Hoebe, K., Kono, D.H., Beutler, B. & Theofilopoulos, A.N. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat. Med. 13, 543–551 (2007).
Banchereau, J. & Pascual, V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25, 383–392 (2006).
Cao, Z., Henzel, W.J. & Gao, X. IRAK: a kinase associated with the interleukin-1 receptor. Science 271, 1128–1131 (1996).
Wesche, H., Henzel, W.J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997).
Uematsu, S. et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction. J. Exp. Med. 201, 915–923 (2005).
Kawai, T. et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5, 1061–1068 (2004).
Honda, K. et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl. Acad. Sci. USA 101, 15416–15421 (2004).
Kollewe, C. et al. Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling. J. Biol. Chem. 279, 5227–5236 (2004).
Honda, K. et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005).
Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005).
Thomas, J.A. et al. Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J. Immunol. 163, 978–984 (1999).
Lu, K.P. & Zhou, X.Z. The prolyl isomerase Pin1: a pivotal new twist in phosphorylation signalling and human disease. Nat. Rev. Mol. Cell Biol. 8, 904–916 (2007).
Yaffe, M.B. et al. Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism. Science 278, 1957–1960 (1997).
Saitoh, T. et al. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat. Immunol. 7, 598–605 (2006).
Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).
Wildemann, D. et al. Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries. J. Med. Chem. 49, 2147–2150 (2006).
Jewell, N.A. et al. Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo. J. Virol. 81, 9790–9800 (2007).
Shen, Z.J., Esnault, S. & Malter, J.S. The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat. Immunol. 6, 1280–1287 (2005).
Lu, P.J., Zhou, X.Z., Shen, M. & Lu, K.P. A function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 283, 1325–1328 (1999).
Hoshino, K. et al. Critical role of IκB kinase α in TLR7/9-induced type I IFN production by conventional dendritic cells. J. Immunol. 184, 3341–3345 (2010).
Li, X. et al. Mutant cells that do not respond to interleukin-1 (IL-1) reveal a novel role for IL-1 receptor-associated kinase. Mol. Cell. Biol. 19, 4643–4652 (1999).
Ranganathan, R., Lu, K.P., Hunter, T. & Noel, J.P. Structural and functional analysis of the mitotic peptidyl-prolyl isomerase Pin1 suggests that substrate recognition is phosphorylation dependent. Cell 89, 875–886 (1997).
Pastorino, L. et al. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440, 528–534 (2006).
Chiang, E.Y., Yu, X. & Grogan, J.L. Immune complex-mediated cell activation from systemic lupus erythematosus and rheumatoid arthritis patients elaborate different requirements for IRAK1/4 kinase activity across human cell types. J. Immunol. 186, 1279–1288 (2011).
Krug, A. et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21, 107–119 (2004).
Dalod, M. et al. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J. Exp. Med. 195, 517–528 (2002).
Delale, T. et al. MyD88-dependent and -independent murine cytomegalovirus sensing for IFN-α release and initiation of immune responses in vivo. J. Immunol. 175, 6723–6732 (2005).
Steinberg, C. et al. The IFN regulatory factor 7-dependent type I IFN response is not essential for early resistance against murine cytomegalovirus infection. Eur. J. Immunol. 39, 1007–1018 (2009).
Ahonen, C.L. et al. Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J. Exp. Med. 199, 775–784 (2004).
Nguyen, K.B. et al. Critical role for STAT4 activation by type 1 interferons in the interferon-γ response to viral infection. Science 297, 2063–2066 (2002).
Honda, K. et al. Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proc. Natl. Acad. Sci. USA 100, 10872–10877 (2003).
Jacob, C.O. et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc. Natl. Acad. Sci. USA 106, 6256–6261 (2009).
Theofilopoulos, A.N., Baccala, R., Beutler, B. & Kono, D.H. Type I interferons (α/β) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307–336 (2005).
Meier, A. et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat. Med. 15, 955–959 (2009).
Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053–2063 (2010).
Rahman, A.H. & Eisenberg, R.A. The role of toll-like receptors in systemic lupus erythematosus. Springer Semin. Immunopathol. 28, 131–143 (2006).
Rahman, A. & Isenberg, D.A. Systemic lupus erythematosus. N. Engl. J. Med. 358, 929–939 (2008).
Gateva, V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).
Lee, T.H. et al. Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance. Nat. Cell Biol. 11, 97–105 (2009).
Ryo, A. et al. Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol. Cell 12, 1413–1426 (2003).
Henry, S.C. et al. Enhanced green fluorescent protein as a marker for localizing murine cytomegalovirus in acute and latent infection. J. Virol. Methods 89, 61–73 (2000).
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.).
The authors declare no competing financial interests.
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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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