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Balancing anti-viral innate immunity and immune homeostasis

Cellular & Molecular Immunology volume 15, pages 408–410 (2018)Cite this article

Immunity against pathogenic challenge requires the engagement of pathogen origin molecular signatures by innate immune sensors that are expressed on various immune and non-immune cells. This microbial pathogen primarily includes various bacteria or viruses. The sensing of viruses leads to the complex interaction of innate immune sensors, which consist of families of evolutionarily conserved germline-encoded molecules known as pathogen recognition receptors (PRRs). This family includes RIG-I-like receptors (RLRs), Toll-like receptors (TLRs), NOD-like receptors (NLRs)1 and DNA sensors (cGAS, IFI16, DAI and AIM2).2 The cytoplasmic helicases RIG-I and MDA5 are the key innate sensors that detect viral genomic RNAs. A few Toll-like receptors (TLRs), such as TLR3, TLR7, TLR8 and TLR9, are present on endocytic vesicles and are crucial for sensing nucleic acid from viruses and inducing the appropriate innate immune responses. However, IFI16, DAI, cGAS and AIM2 play an important role in the recognition of viral genomic DNA. Upon pathogen challenge, these PRRs recruit several adaptors, including IPS-1 (also known as MAVS, VISA or CARDIF),3,4 MyD88, TRIF and STING, to initiate a cascade of signaling events. These events converge at the inhibitor IκB kinase complexes, which are composed of either IKKα, IKKβ, and IKKγ or the IκB kinases TBK1 and IKKɛ/IKKi. TBK1 and IKKɛ phosphorylate the transcription factor, interferon regulatory factor (IRF) 3, thereby initiating its dimerization, nuclear translocation and subsequent production of type I and III IFNs and pro-inflammatory cytokines, which trigger the transcription of interferon-stimulated genes to restrict viral spread.2 These kinases are dynamically regulated via the post-translational modifications that occur during viral infection (that is, polyubiquitination) by TRAF3 or other similar E3 ligases. The modifications are linked to the expression and stability of the signaling complex, resulting in a downstream signal for the anti-viral state.2 Dysregulation of type I IFNs may lead to various inflammatory/autoimmune diseases.5,6 To avoid immunopathology, the sensing of viruses and signaling pathways is tightly regulated at the transcriptional and translational levels and determines the duration and magnitude of immune responses to ensure viral clearance and immune homeostasis.

Recent years have witnessed such modes of regulation; for example, miRNAs have emerged as one of the key players to regulate gene expression by targeting the 3′-untranslated regions (UTR) of mRNA, resulting in degradation via cleavage, translational repression and deadenylation.7 Similarly, phosphorylation and ubiquitination are well-characterized post-translational modifications that also control the intensity of the immune responses. Moreover, the anti-viral innate immune system is equipped with several molecules to down-regulate the innate anti-viral response. The downregulation may be caused by direct interactions or post-translational modifications, such as peptidyl-prolyl isomerase PIN1, FoxO1 and TRIM21, which dampen the activation of IRF3 (Table 1).8,9,10,11,12,13,14,15,16 Given the vital roles of IRF3 in the expression of an anti-viral state, via the production of pro-inflammatory molecules and type I and III IFNs, research is now focused primarily on identifying novel regulators (positive and negative), with the aim of finding new therapeutic targets during viral infection and combatting several autoimmune diseases.5

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References

  1. Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009; 21: 317–337.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Kumar H, Kawai T, Kato H, Sato S, Takahashi K, Coban C et al. Essential role of IPS-1 in innate immune responses against RNA viruses. J Exp Med 2006; 203: 1795–1803.

    Article  CAS  Google Scholar 

  4. Sun Q, Sun L, Liu HH, Chen X, Seth RB, Forman J et al. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 2006; 24: 633–642.

    Article  CAS  Google Scholar 

  5. Di Domizio J, Cao W. Fueling autoimmunity: type I interferon in autoimmune diseases. Expert Rev Clin Immunol 2013; 9: 201–210.

    Article  CAS  Google Scholar 

  6. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol 2014; 14: 36–49.

    Article  CAS  Google Scholar 

  7. Ingle H, Kumar S, Raut AA, Mishra A, Kulkarni DD, Kameyama T et al. The microRNA miR-485 targets host and influenza virus transcripts to regulate antiviral immunity and restrict viral replication. Sci Signal 2015; 8: ra126.

    Article  Google Scholar 

  8. Lei CQ, Zhang Y, Xia T, Jiang LQ, Zhong B, Shu HB. FoxO1 negatively regulates cellular antiviral response by promoting degradation of IRF3. J Biol Chem 2013; 288: 12596–12604.

    Article  CAS  Google Scholar 

  9. Saitoh T, Tun-Kyi A, Ryo A, Yamamoto M, Finn G, Fujita T et al. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat Immunol 2006; 7: 598–605.

    Article  CAS  Google Scholar 

  10. Yang K, Shi HX, Liu XY, Shan YF, Wei B, Chen S et al. TRIM21 is essential to sustain IFN regulatory factor 3 activation during antiviral response. J Immunol 2009; 182: 3782–3792.

    Article  CAS  Google Scholar 

  11. Saitoh T, Yamamoto M, Miyagishi M, Taira K, Nakanishi M, Fujita T et al. A20 is a negative regulator of IFN regulatory factor 3 signaling. J Immunol 2005; 174: 1507–1512.

    Article  CAS  Google Scholar 

  12. Li Y, Li C, Xue P, Zhong B, Mao AP, Ran Y et al. ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. Proc Natl Acad Sci USA 2009; 106: 7945–7950.

    Article  CAS  Google Scholar 

  13. Yu Y, Hayward GS. The ubiquitin E3 ligase RAUL negatively regulates type I interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity 2010; 33: 863–877.

    Article  CAS  Google Scholar 

  14. Ren Y, Zhao Y, Lin D, Xu X, Zhu Q, Yao J et al. The type I interferon-IRF7 axis mediates transcriptional expression of Usp25 gene. J Biol Chem 2016; 291: 13206–13215.

    Article  CAS  Google Scholar 

  15. Li S, Zhu M, Pan R, Fang T, Cao YY, Chen S et al. The tumor suppressor PTEN has a critical role in antiviral innate immunity. Nat Immunol 2016; 17: 241–249.

    Article  CAS  Google Scholar 

  16. Wang S, Sun X, Yi C, Zhang D, Lin X, Sun X et al. AGO2 negatively regulates type I interferon signaling pathway by competition binding IRF3 with CBP/p300. Front Cell Infect Microbiol 2017; 7: 195.

    Article  Google Scholar 

  17. Wang S, Xie F, Chu F, Zhang Z, Yang B, Dai T et al. YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKKvarepsilon-mediated phosphorylation. Nat Immunol 2017; 18: 733–743.

    Article  CAS  Google Scholar 

  18. Zhang Q, Meng F, Chen S, Plouffe SW, Wu S, Liu S et al. Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat Cell Biol 2017; 19: 362–374.

    Article  CAS  Google Scholar 

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  1. Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, 462066, India

    Shalabh Mishra & Himanshu Kumar

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Correspondence to Himanshu Kumar.

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Mishra, S., Kumar, H. Balancing anti-viral innate immunity and immune homeostasis. Cell Mol Immunol 15, 408–410 (2018). https://doi.org/10.1038/cmi.2017.98

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