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Review
. 2015 Oct 30;290(44):26412-21.
doi: 10.1074/jbc.R115.652289. Epub 2015 Sep 9.

The emerging role of nuclear viral DNA sensors

Benjamin A Diner  1 , Krystal K Lum  1 , Ileana M Cristea  2
Affiliations
Review

The emerging role of nuclear viral DNA sensors

Benjamin A Diner et al. J Biol Chem. .

Abstract

Detecting pathogenic DNA by intracellular receptors termed "sensors" is critical toward galvanizing host immune responses and eliminating microbial infections. Emerging evidence has challenged the dogma that sensing of viral DNA occurs exclusively in sub-cellular compartments normally devoid of cellular DNA. The interferon-inducible protein IFI16 was shown to bind nuclear viral DNA and initiate immune signaling, culminating in antiviral cytokine secretion. Here, we review the newly characterized nucleus-originating immune signaling pathways, their links to other crucial host defenses, and unique mechanisms by which viruses suppress their functions. We frame these findings in the context of human pathologies associated with nuclear replicating DNA viruses.

Keywords: IFI16; IFIX; STING; cGAS; cytokine induction; infectious disease; protein-DNA interaction; signaling; viral DNA sensing; viral immunology.

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Figures

FIGURE 1.
FIGURE 1.
Cooperative binding of IFI16 is mediated by HIN domains binding viral dsDNA and pyrin domains oligomerizing. A, crystal structure of HIN-b domains (yellow, orange, blue, and green) binding to viral dsDNA (red). Mutations at highlighted amino acids impaired DNA binding (adapted from Ref. 30). PDB 3RNU, Protein Data Bank ID 3RNU. B, model of IFI16 binding to viral DNA in a length-dependent manner (one IFI16 molecule per 15 bp of viral DNA) (adapted from Ref. 32). C, post-translational modifications identified on IFI16 (36, 85, 86).
FIGURE 2.
FIGURE 2.
Nucleus-originating immune signaling is activated upon sensing of herpesviral dsDNA. Following viral entry into a host cell, the capsid extrudes viral dsDNA into the nucleus (1). Nuclear viral DNA is bound directly to DNA sensors IFI16 and IFIX (2). IFI16 signals to STING via a mechanism that has yet to be elucidated (3a). cGAS was also observed in the nucleus following HSV-1 infection and shown to stabilize IFI16. Upon activation and dimerization of STING, TBK-1 is phosphorylated (4), resulting in the phosphorylation of IRF3 and NF-κB, which translocate back into the nucleus to induce the expression of antiviral cytokines (5). Upon binding nuclear viral dsDNA, IFI16 also associates with ASC to form mature inflammasomes in the cytoplasm, processing pro-inflammatory cytokines (3b). It remains to be investigated whether cGAS may also sense viral DNA within the nucleus to produce cyclic GMP-AMP, which binds directly to STING (3c). Solid arrows depict experimentally demonstrated pathways, and dotted arrows illustrate other possible mechanisms. Casp-1, caspase-1; ER, endoplasmic reticulum.
FIGURE 3.
FIGURE 3.
Herpesviruses have evolved distinct strategies for suppressing IFI16 functions during infection. The HSV-1 E3 ubiquitin ligase ICP0, directly or indirectly, catalyzes the proteasomal degradation of IFI16 (left). The HCMV major tegument protein pUL83 binds directly to the PY domain of IFI16, inhibiting IFI16 oligomerization and consequential immune signaling (right).
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References

    1. Arzumanyan A., Reis H. M., and Feitelson M. A. (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat. Rev. Cancer 13, 123–135 - PubMed
    1. McFadden K., and Luftig M. A. (2013) Interplay between DNA tumor viruses and the host DNA damage response. Curr. Top. Microbiol. Immunol. 371, 229–257 - PMC - PubMed
    1. Moens U., Rasheed K., Abdulsalam I., and Sveinbjørnsson B. (2015) The role of Merkel cell polyomavirus and other human polyomaviruses in emerging hallmarks of cancer. Viruses 7, 1871–1901 - PMC - PubMed
    1. Weinstock H., Berman S., and Cates W. Jr. (2004) Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect. Sex. Reprod. Health 36, 6–10 - PubMed
    1. Kojaoghlanian T., Flomenberg P., and Horwitz M. S. (2003) The impact of adenovirus infection on the immunocompromised host. Rev. Med. Virol. 13, 155–171 - PubMed

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