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RNA degradation in antiviral immunity and autoimmunity.

Rigby RE, Rehwinkel J - Trends Immunol. (2015)

Bottom Line: Post-transcriptional control determines the fate of cellular RNA molecules.Recent findings have revealed a role for NMD in targeting viral RNA molecules, thereby restricting virus infection.Interestingly, NMD is also linked to immune responses at another level: mutations affecting the NMD or RNA exosome machineries cause chronic activation of defence programmes, resulting in autoimmune phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

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Nucleic acid detection by pattern recognition receptors. Virus infection delivers nucleic acids into infected cells. (Left) DNA is detected in the cytoplasm by cyclic GMP-AMP synthase (cGAS), which then uses ATP and GTP to generate cyclic GMP-AMP (cGAMP). This second messenger subsequently binds to the ER-associated protein STING which in turn activates TBK1. This kinase then phosphorylates the transcription factor IRF3, which forms a dimer and translocates to the cell nucleus to induce type I IFN gene transcription. Aside from cGAS, additional proteins including IFI16, DDX41, MRE11, and DNA-PK may participate in cytosolic DNA recognition [51] but are not shown here for simplicity. (Centre) Viral nucleic acids are also detected in endosomal compartments by TLR9 (DNA), TLR3 (dsRNA), and TLR7/8 (ssRNA). These PRRs signal through the adaptor proteins MyD88 or TRIF to activate the kinases IKKα, TBK1, and IKKɛ resulting in phosphorylation, dimerisation and translocation of IRF3 or IRF7. (Right) RNA in the cytoplasm of infected cells is recognised by RIG-I and MDA5, which interact with the mitochondrial protein MAVS to trigger TBK1/IKKɛ. Please note that a variety of other proteins are involved in signal transduction that are not shown here for clarity.
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fig0010: Nucleic acid detection by pattern recognition receptors. Virus infection delivers nucleic acids into infected cells. (Left) DNA is detected in the cytoplasm by cyclic GMP-AMP synthase (cGAS), which then uses ATP and GTP to generate cyclic GMP-AMP (cGAMP). This second messenger subsequently binds to the ER-associated protein STING which in turn activates TBK1. This kinase then phosphorylates the transcription factor IRF3, which forms a dimer and translocates to the cell nucleus to induce type I IFN gene transcription. Aside from cGAS, additional proteins including IFI16, DDX41, MRE11, and DNA-PK may participate in cytosolic DNA recognition [51] but are not shown here for simplicity. (Centre) Viral nucleic acids are also detected in endosomal compartments by TLR9 (DNA), TLR3 (dsRNA), and TLR7/8 (ssRNA). These PRRs signal through the adaptor proteins MyD88 or TRIF to activate the kinases IKKα, TBK1, and IKKɛ resulting in phosphorylation, dimerisation and translocation of IRF3 or IRF7. (Right) RNA in the cytoplasm of infected cells is recognised by RIG-I and MDA5, which interact with the mitochondrial protein MAVS to trigger TBK1/IKKɛ. Please note that a variety of other proteins are involved in signal transduction that are not shown here for clarity.

Mentions: Nucleic acids are potent activators of the innate immune response in mammals and numerous specialised nucleic acid-sensing PRRs and their downstream signalling cascades have been identified [51] (Figure 2). The detection of viral and bacterial nucleic acids triggers a powerful innate immune response that is characterised by the production of type I interferons (IFNs). Type I IFNs signal via the type I interferon receptor to activate transcription of hundreds of ISGs, many of which restrict virus infection [35]. This thereby induces an antiviral state both in the infected cell as well as in the surrounding tissue microenvironment. The type I IFN-induced antiviral state prevents virus replication and spread and constitutes an important barrier to infection; this is evident, for example, from the fact almost every mammalian virus counteracts and/or evades the IFN response [52,53]. Moreover, type I IFNs facilitate cell-mediated innate and adaptive immune responses [54,55]. Type I IFNs are therefore crucial to successful immunity against virus infection.


RNA degradation in antiviral immunity and autoimmunity.

Rigby RE, Rehwinkel J - Trends Immunol. (2015)

Nucleic acid detection by pattern recognition receptors. Virus infection delivers nucleic acids into infected cells. (Left) DNA is detected in the cytoplasm by cyclic GMP-AMP synthase (cGAS), which then uses ATP and GTP to generate cyclic GMP-AMP (cGAMP). This second messenger subsequently binds to the ER-associated protein STING which in turn activates TBK1. This kinase then phosphorylates the transcription factor IRF3, which forms a dimer and translocates to the cell nucleus to induce type I IFN gene transcription. Aside from cGAS, additional proteins including IFI16, DDX41, MRE11, and DNA-PK may participate in cytosolic DNA recognition [51] but are not shown here for simplicity. (Centre) Viral nucleic acids are also detected in endosomal compartments by TLR9 (DNA), TLR3 (dsRNA), and TLR7/8 (ssRNA). These PRRs signal through the adaptor proteins MyD88 or TRIF to activate the kinases IKKα, TBK1, and IKKɛ resulting in phosphorylation, dimerisation and translocation of IRF3 or IRF7. (Right) RNA in the cytoplasm of infected cells is recognised by RIG-I and MDA5, which interact with the mitochondrial protein MAVS to trigger TBK1/IKKɛ. Please note that a variety of other proteins are involved in signal transduction that are not shown here for clarity.
© Copyright Policy - CC BY
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fig0010: Nucleic acid detection by pattern recognition receptors. Virus infection delivers nucleic acids into infected cells. (Left) DNA is detected in the cytoplasm by cyclic GMP-AMP synthase (cGAS), which then uses ATP and GTP to generate cyclic GMP-AMP (cGAMP). This second messenger subsequently binds to the ER-associated protein STING which in turn activates TBK1. This kinase then phosphorylates the transcription factor IRF3, which forms a dimer and translocates to the cell nucleus to induce type I IFN gene transcription. Aside from cGAS, additional proteins including IFI16, DDX41, MRE11, and DNA-PK may participate in cytosolic DNA recognition [51] but are not shown here for simplicity. (Centre) Viral nucleic acids are also detected in endosomal compartments by TLR9 (DNA), TLR3 (dsRNA), and TLR7/8 (ssRNA). These PRRs signal through the adaptor proteins MyD88 or TRIF to activate the kinases IKKα, TBK1, and IKKɛ resulting in phosphorylation, dimerisation and translocation of IRF3 or IRF7. (Right) RNA in the cytoplasm of infected cells is recognised by RIG-I and MDA5, which interact with the mitochondrial protein MAVS to trigger TBK1/IKKɛ. Please note that a variety of other proteins are involved in signal transduction that are not shown here for clarity.
Mentions: Nucleic acids are potent activators of the innate immune response in mammals and numerous specialised nucleic acid-sensing PRRs and their downstream signalling cascades have been identified [51] (Figure 2). The detection of viral and bacterial nucleic acids triggers a powerful innate immune response that is characterised by the production of type I interferons (IFNs). Type I IFNs signal via the type I interferon receptor to activate transcription of hundreds of ISGs, many of which restrict virus infection [35]. This thereby induces an antiviral state both in the infected cell as well as in the surrounding tissue microenvironment. The type I IFN-induced antiviral state prevents virus replication and spread and constitutes an important barrier to infection; this is evident, for example, from the fact almost every mammalian virus counteracts and/or evades the IFN response [52,53]. Moreover, type I IFNs facilitate cell-mediated innate and adaptive immune responses [54,55]. Type I IFNs are therefore crucial to successful immunity against virus infection.

Bottom Line: Post-transcriptional control determines the fate of cellular RNA molecules.Recent findings have revealed a role for NMD in targeting viral RNA molecules, thereby restricting virus infection.Interestingly, NMD is also linked to immune responses at another level: mutations affecting the NMD or RNA exosome machineries cause chronic activation of defence programmes, resulting in autoimmune phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

Show MeSH
Related in: MedlinePlus