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Regulation of antiviral innate immunity by deubiquitinase CYLD

Cellular & Molecular Immunology volume 8, pages 502–504 (2011)Cite this article

Abstract

An antiviral innate immune response involves induction of type I interferons (IFNs) and their subsequent autocrine and paracrine actions, but the underlying regulatory mechanisms are incompletely understood. Here we report that CYLD, a deubiquitinase that specifically digests lysine 63-linked ubiquitin chains, is required for antiviral host defense. Loss of CYLD renders mice considerably more susceptible to infection by vesicular stomatitis virus (VSV). Consistently, CYLD-deficient dendritic cells are more sensitive to VSV infection. This functional defect was not due to lack of type I IFN production but rather because of attenuated IFN receptor signaling. In the absence of CYLD, IFN-β is ineffective in the induction of antiviral genes and protection of cells from viral infection. These findings establish CYLD as a novel regulator of antiviral innate immunity and suggest a role for CYLD in regulating IFN receptor signaling.

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References

  1. Kumar H, Kawai T, Akira S . Pathogen recognition by the innate immune system. Int Rev Immunol 2011; 30: 16–34.

    Article  CAS  Google Scholar 

  2. Theofilopoulos AN, Baccala R, Beutler B, Kono DH . Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 2005; 23: 307–336.

    Article  CAS  Google Scholar 

  3. Nakhaei P, Genin P, Civas A, Hiscott J . RIG-I-like receptors: sensing and responding to RNA virus infection. Semin Immunol 2009; 21: 215–222.

    Article  CAS  Google Scholar 

  4. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 2007; 446: 916–920.

    Article  CAS  Google Scholar 

  5. Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A et al. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 2010; 141: 315–330.

    Article  CAS  Google Scholar 

  6. Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cárdenas WB, Yount JS et al. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep 2008; 9: 930–936.

    Article  CAS  Google Scholar 

  7. Zhang M, Wu X, Lee AJ, Jin W, Chang M, Wright A et al. Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem 2008; 283: 18621–18626.

    Article  CAS  Google Scholar 

  8. Sun SC . CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation. Cell Death Differ 2010; 17: 25–34.

    Article  CAS  Google Scholar 

  9. Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC et al. Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 2006; 7: 411–417.

    Article  CAS  Google Scholar 

  10. Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF et al. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 2007; 204: 1475–1485.

    Article  CAS  Google Scholar 

  11. Reiley W, Zhang M, Sun SC . Tumor suppressor negatively regulates JNK signaling pathway downstream of TNFR members. J Biol Chem 2004; 279: 55161–55167.

    Article  CAS  Google Scholar 

  12. Fernandez M, Porosnicu M, Markovic D, Barber GN . Genetically engineered vesicular stomatitis virus in gene therapy: application for treatment of malignant disease. J Virol 2002; 76: 895–904.

    Article  CAS  Google Scholar 

  13. Uhlik M, Good L, Xiao G, Harhaj EW, Zandi E, Karin M et al. NF-kappaB-inducing kinase and IkappaB kinase participate in human T-cell leukemia virus I Tax-mediated NF-kappaB activation. J Biol Chem 1998; 273: 21132–21136.

    Article  CAS  Google Scholar 

  14. Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR et al. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 2000; 13: 129–141.

    Article  CAS  Google Scholar 

  15. Stojdl DF, Abraham N, Knowles S, Marius R, Brasey A, Lichty BD et al. The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. J Virol 2000; 74: 9580–9585. .

    Article  CAS  Google Scholar 

  16. Tenoever BR, Ng SL, Chua MA, McWhirter SM, García-Sastre A, Maniatis T . Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science 2007; 315: 1274–1278.

    Article  CAS  Google Scholar 

  17. Tsichritzis T, Gaentzsch PC, Kosmidis S, Brown AE, Skoulakis EM, Ligoxygakis P et al. A Drosophila ortholog of the human cylindromatosis tumor suppressor gene regulates triglyceride content and antibacterial defense. Development 2007; 134: 2605–2614.

    Article  CAS  Google Scholar 

  18. Kumar KG, Barriere H, Carbone CJ, Liu J, Swaminathan G, Xu P et al. Site-specific ubiquitination exposes a linear motif to promote interferon-alpha receptor endocytosis. J Cell BIol 2007; 179: 935–950.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Glen Barber for VSV strain. This study was supported by the National Institutes of Health grant AI064639.

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Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Minying Zhang, Andrew J Lee, Xuefeng Wu & Shao-Cong Sun

  2. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Minying Zhang

  3. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, La Jolla, CA, USA

    Xuefeng Wu

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  1. Minying Zhang
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Correspondence to Shao-Cong Sun.

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Zhang, M., Lee, A., Wu, X. et al. Regulation of antiviral innate immunity by deubiquitinase CYLD. Cell Mol Immunol 8, 502–504 (2011). https://doi.org/10.1038/cmi.2011.42

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