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Virus-induced accumulation of intracellular bile acids activates the TGR5-β-arrestin-SRC axis to enable innate antiviral immunity

Abstract

The mechanisms on metabolic regulation of immune responses are still elusive. We show here that viral infection induces immediate-early NF-κB activation independent of viral nucleic acid-triggered signaling, which triggers a rapid transcriptional induction of bile acid (BA) transporter and rate-limiting biosynthesis enzymes as well as accumulation of intracellular BAs in divergent cell types. The accumulated intracellular BAs activate SRC kinase via the TGR5-GRK-β-arrestin axis, which mediates tyrosine phosphorylation of multiple antiviral signaling components including RIG-I, VISA/MAVS, MITA/STING, TBK1 and IRF3. The tyrosine phosphorylation of these components by SRC conditions for efficient innate antiviral immune response. Consistently, TGR5 deficiency impairs innate antiviral immunity, whereas BAs exhibit potent antiviral activity in wild-type but not TGR5-deficient cells and mice. Our findings reveal an intrinsic and universal role of intracellular BA metabolism in innate antiviral immunity.

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References

  1. 1.

    Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

  2. 2.

    Crowl, J. T., Gray, E. E., Pestal, K., Volkman, H. E. & Stetson, D. B. Intracellular nucleic acid detection in autoimmunity. Annu. Rev. Immunol. 35, 313–336 (2017).

  3. 3.

    Hu, M. M. & Shu H. B. Cytoplasmic mechanisms of recognition and defense of microbial nucleic acids. Annu. Rev. Cell Dev. Biol. 34, 357–379 (2018).

  4. 4.

    Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682 (2005).

  5. 5.

    Kawai, T. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6, 981–988 (2005).

  6. 6.

    Xu, L. G. et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19, 727–740 (2005).

  7. 7.

    Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

  8. 8.

    Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

  9. 9.

    Gao, P. et al. Cyclic [G(2’,5’)pA(3’,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153, 1094–1107 (2013).

  10. 10.

    Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538–550 (2008).

  11. 11.

    Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

  12. 12.

    Cai, X., Chiu, Y. H. & Chen, Z. J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell 54, 289–296 (2014).

  13. 13.

    Chiang, C. & Gack, M. U. Post-translational control of intracellular pathogen sensing pathways. Trends Immunol. 38, 39–52 (2017).

  14. 14.

    Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu. Rev. Immunol. 32, 609–634 (2014).

  15. 15.

    Kelly, B. & O’Neill, L. A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25, 771–784 (2015).

  16. 16.

    Russell, D. W. Fifty years of advances in bile acid synthesis and metabolism. J. Lipid Res. 50, S120–S125 (2009).

  17. 17.

    de Aguiar Vallim, T. Q., Tarling, E. J. & Edwards, P. A. Pleiotropic roles of bile acids in metabolism. Cell. Metab. 17, 657–669 (2013).

  18. 18.

    Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003).

  19. 19.

    Maruyama, T. et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714–719 (2002).

  20. 20.

    Pols, T. W., Noriega, L. G., Nomura, M., Auwerx, J. & Schoonjans, K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J. Hepatol. 54, 1263–1272 (2011).

  21. 21.

    Gadaleta, R. M., Cariello, M., Sabba, C. & Moschetta, A. Tissue-specific actions of FXR in metabolism and cancer. Biochim. Biophys. Acta 1851, 30–39 (2015).

  22. 22.

    Guo, C. et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45, 802–816 (2016).

  23. 23.

    Patman, G. Hepatitis: HBV infection alters bile acid metabolism gene profile. Nat. Rev. Gastroenterol. Hepatol. 11, 332 (2014).

  24. 24.

    Perino, A. & Schoonjans, K. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol. Sci. 36, 847–857 (2015).

  25. 25.

    Santoro, M. G., Rossi, A. & Amici, C. NF-kappaB and virus infection: who controls whom. EMBO J. 22, 2552–2560 (2003).

  26. 26.

    Premont, R. T. & Gainetdinov, R. R. Physiological roles of G protein-coupled receptor kinases and arrestins. Annu. Rev. Physiol. 69, 511–534 (2007).

  27. 27.

    Yang, F. et al. Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and (19)F-NMR. Nat. Commun. 6, 8202 (2015).

  28. 28.

    Cooper, J. A. & Howell, B. The when and how of Src regulation. Cell 73, 1051–1054 (1993).

  29. 29.

    Li, X., et al. The tyrosine kinase Src promotes phosphorylation of the kinase TBK1 to facilitate type I interferon production after viral infection. Sci. Signal 10, eaae0435 (2017).

  30. 30.

    Russell, D. W. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72, 137–174 (2003).

  31. 31.

    Soliman, M., et al. Phosphatidylinositol 3-Kinase/Akt and MEK/ERK signaling pathways facilitate sapovirus trafficking and late endosomal acidification for viral uncoating in LLC-PK cells. J. Virol. 92, e01674–18 (2018).

  32. 32.

    Masyuk, A. I. et al. Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1013–G1024 (2013).

  33. 33.

    Schlessinger, J. New roles for Src kinases in control of cell survival and angiogenesis. Cell 100, 293–296 (2000).

  34. 34.

    Hu, M. M., Liao, C. Y., Yang, Q., Xie, X. Q. & Shu, H. B. Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5. J. Exp. Med. 214, 973–989 (2017).

  35. 35.

    Hu, M. M. et al. Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor STING to regulate the kinetics of response to DNA virus. Immunity 45, 555–569 (2016).

  36. 36.

    Hu, M. M. et al. TRIM38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. J. Immunol. 195, 4415–4425 (2015).

  37. 37.

    Zhu, Q. F. et al. Analysis of cytochrome P450 metabolites of arachidonic acid by stable isotope probe labeling coupled with ultra high-performance liquid chromatography/mass spectrometry. J. Chromatogr. A 1410, 154–163 (2015).

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Acknowledgements

We thank Dr. Rui Xiao for his assistant on CHIP assays analysis. This work was supported by grants from the State Key R&D Program of China (2017YFA0505800, 2016YFA0502102), and the National Natural Science Foundation of China (31830024, 31771555, 31630045, 31521091, 31671465, and 31800728), National Postdoctoral Program for Innovative Talents (BX201600116) and China Postdoctoral Science Foundation (2017M620334).

Author information

H.B.S. and M.M.H. conceived and designed the study; M.M.H., W.R.H., P.G., Q.Y., K.H., and L.B.C. performed the experiments; H.B.S., M.M.H., Q.Y., S.L. and Y.Q.F. analyzed the data. M.M.H. and H.B.S. wrote the manuscript.

Correspondence to Ming-Ming Hu or Hong-Bing Shu.

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The authors declare no competing interests.

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