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Relief of YAP-mediated inhibition by IKKɛ promotes innate antiviral immunity

Cellular & Molecular Immunology volume 15, pages 642–644 (2018)Cite this article

The innate immune response to invading viruses is critical for the mounting of protective immunity, in which type I interferons (IFN), for example, IFN-α and β, are potent effector molecules.1 Most cell types, particularly fibroblasts and epithelial cells, produce IFN-β, whereas hematopoietic cells, notably plasmacytoid dendritic cells, are the predominant sources of IFN-α. IFNs potently stimulate a variety of innate and adaptive immune cells, including macrophages, NK cells and T cells. The binding of type I IFN to its cognate receptor triggers the activation of the Janus kinase signal transducer and activator of transcription pathway, which results in the transcription of IFN-stimulated genes that play key roles in host resistance to viral infections. The production of type I IFN is finely controlled by diverse host factors to trigger tailored immune responses that are suitable for host defense and survival.1 This balanced production of type I IFN is critical for protection against viral infections, as their defective or excessive production leads to chronic infection or autoimmune and/or inflammatory diseases, respectively. In this respect, a greater understanding of the mechanisms and the identification of novel host factors that govern type I IFN production are important for elucidating host antiviral defenses and developing rational therapies for effective viral eradication that do not damage the host.

Innate antiviral immunity is initiated by the engagement of pattern recognition receptors (PRRs) that are present on the cell surface or within distinct intracellular compartments.2,3 The prototypical pathogen-associated molecular patterns of viruses are nucleic acids, for example, viral RNA and DNA, which can be recognized by a number of PRRs, such as endosomal Toll-like receptors (TLRs), cytosolic RIG-I-like receptors (RLRs) and cytosolic sensors of DNA, including cyclic GMP-AMP synthase (cGAS), DExD/H box family helicase (DDX41) and IFN-inducible protein (IFI16).2,3 With the exceptions of some viruses that possess the ability to directly enter the cytoplasm, for example, HIV and herpes simplex virus (HSV), the entry of viruses is mainly mediated by an endocytic pathway. Endocytosed viruses are first trafficked to endocytic compartments called endosomes and then penetrate the endosomal membrane to release their nucleic acids into the cytoplasm. These viral nucleic acids in the endosome are recognized by the RNA sensors TLR3, TLR7 and TLR8 and the DNA sensor TLR9, whereas those in the cytoplasm are recognized by the RNA sensors RIG-I and MDA5 and the DNA sensor cGAS. Upon recognition of viral nucleic acids, these PRRs recruit adapter molecules, such as MyD88, TRIF, MAVS and STING. The MyD88-dependent responses of TLR7, TLR8 and TLR9 lead to the expression of type I IFN via IRF7 activation, and the TRIF recruited by TLR3, MAVS recruited by RLRs and STING recruited cGAS trigger the activation of the IKK-related kinases IKKɛ and TBK1, which drive IRF3 activation and type I IFN production.

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Acknowledgements

This study was supported by the Intelligent Synthetic Biology Center of the Global Frontier Project funded by the Ministry of Education, Science and Technology (2013-0073185) and Grants from the National Research Foundation of Korea (2016R1A2B4010300).

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Authors and Affiliations

  1. Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, 05505, Seoul, Korea

    Nayoung Kim & Yun-Yong Park

  2. Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 05505, Seoul, Korea

    Nayoung Kim & Yun-Yong Park

  3. Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, 05505, Seoul, Korea

    Chul Hyun Joo & Hun Sik Kim

  4. Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, 05505, Seoul, Korea

    Hun Sik Kim

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Kim, N., Park, YY., Joo, C. et al. Relief of YAP-mediated inhibition by IKKɛ promotes innate antiviral immunity. Cell Mol Immunol 15, 642–644 (2018). https://doi.org/10.1038/cmi.2017.97

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