Function and Regulation of Nuclear DNA Sensors During Viral Infection and Tumorigenesis

IFI16, hnRNPA2B1, and nuclear cGAS are nuclear-located DNA sensors that play important roles in initiating host antiviral immunity and modulating tumorigenesis. IFI16 triggers innate antiviral immunity, inflammasome, and suppresses tumorigenesis by recognizing double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), damaged nuclear DNA, or cooperatively interacting with multiple tumor suppressors such as p53 and BRCA1. hnRNPA2B1 initiates interferon (IFN)-α/β production and enhances STING-dependent cytosolic antiviral signaling by directly binding viral dsDNA from invaded viruses and facilitating N6-methyladenosine (m6A) modification of cGAS, IFI16, and STING mRNAs. Nuclear cGAS is recruited to double-stranded breaks (DSBs), suppresses DNA repair, and promotes tumorigenesis. This review briefly describes the nuclear functions of IFI16, hnRNPA2B1, and cGAS, and summarizes the transcriptional, post-transcriptional, and post-translational regulation of these nuclear DNA sensors.

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USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS

Nature Communications ◽

10.1038/s41467-021-23219-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jinxiu Hou ◽

Lulu Han ◽

Ze Zhao ◽

Huiqing Liu ◽

Lei Zhang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Sendai Virus ◽

Rna Virus ◽

Antiviral Immunity ◽

Encephalomyocarditis Virus ◽

Type I ◽

Antiviral Signaling ◽

Central Function ◽

Adaptor Molecule ◽

Innate Antiviral Immunity

AbstractActivation of MAVS, an adaptor molecule in Rig-I-like receptor (RLR) signaling, is indispensable for antiviral immunity, yet the molecular mechanisms modulating MAVS activation are not completely understood. Ubiquitination has a central function in regulating the activity of MAVS. Here, we demonstrate that a mitochondria-localized deubiquitinase USP18 specifically interacts with MAVS, promotes K63-linked polyubiquitination and subsequent aggregation of MAVS. USP18 upregulates the expression and production of type I interferon following infection with Sendai virus (SeV) or Encephalomyocarditis virus (EMCV). Mice with a deficiency of USP18 are more susceptible to RNA virus infection. USP18 functions as a scaffold protein to facilitate the re-localization of TRIM31 and enhances the interaction between TRIM31 and MAVS in mitochondria. Our results indicate that USP18 functions as a post-translational modulator of MAVS-mediated antiviral signaling.

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Faculty Opinions recommendation of Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1085873.540733 ◽

2007 ◽

Author(s):

Richard L Stevens

Keyword(s):

Respiratory Syncytial Virus ◽

Antiviral Immunity ◽

Syncytial Virus ◽

Innate Antiviral Immunity

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NME3 Regulates Mitochondria to Reduce ROS-Mediated Genome Instability

International Journal of Molecular Sciences ◽

10.3390/ijms21145048 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5048

Author(s):

Chih-Wei Chen ◽

Ning Tsao ◽

Wei Zhang ◽

Zee-Fen Chang

Keyword(s):

Oxidative Stress ◽

Dna Repair ◽

Genome Stability ◽

Nuclear Dna ◽

Genome Instability ◽

Mitochondrial Fission ◽

Nucleoside Diphosphate Kinase ◽

Mitochondrial Fusion ◽

Mitochondrial Outer Membrane ◽

Mitochondrial Oxidative Stress

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family that binds to the mitochondrial outer membrane to stimulate mitochondrial fusion. In this study, we showed that NME3 knockdown delayed DNA repair without reducing the cellular levels of nucleotide triphosphates. Further analyses revealed that NME3 knockdown increased fragmentation of mitochondria, which in turn led to mitochondrial oxidative stress-mediated DNA single-strand breaks (SSBs) in nuclear DNA. Re-expression of wild-type NME3 or inhibition of mitochondrial fission markedly reduced SSBs and facilitated DNA repair in NME3 knockdown cells, while expression of N-terminal deleted mutant defective in mitochondrial binding had no rescue effect. We further showed that disruption of mitochondrial fusion by knockdown of NME4 or MFN1 also caused mitochondrial oxidative stress-mediated genome instability. In conclusion, the contribution of NME3 to redox-regulated genome stability lies in its function in mitochondrial fusion.

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Epigenetic regulation of frog innate immunity: Discovery of frog microRNAs associated with antiviral responses and ranavirus infection using a Xenopus laevis skin epithelial-like cell line

10.1101/2021.06.29.450442 ◽

2021 ◽

Author(s):

Lauren A. Todd ◽

Maxwell P. Bui-Marinos ◽

Barbara A. Katzenback

Keyword(s):

Xenopus Laevis ◽

Cell Line ◽

Antiviral Immunity ◽

Type I Interferons ◽

Poly I:C ◽

Type I ◽

Frog Virus ◽

Interferon Stimulated Genes ◽

Antiviral Responses ◽

Innate Antiviral Immunity

Epigenetic regulators such as microRNAs are emerging as conserved regulators of innate antiviral immunity in vertebrates, yet their roles in amphibian antiviral responses remain uncharacterized. We profiled changes in microRNA expressions in the Xenopus laevis skin epithelial–like cell line Xela DS2 in response to poly(I:C) – an analogue of double-stranded viral RNA and inducer of type I interferons – or frog virus 3 (FV3), an immunoevasive virus associated with amphibian mortality events. We sequenced small RNA libraries generated from untreated, poly(I:C)–treated, and FV3–infected cells. We detected 136 known X. laevis microRNAs and discovered 133 novel X. laevis microRNAs. Sixty–five microRNAs were differentially expressed in response to poly(I:C), many of which were predicted to target regulators of antiviral pathways such as cGAS–STING, RIG–I/MDA–5, TLR signaling, and type I interferon signaling, as well as products of these pathways (NF–κB–induced and interferon-stimulated genes). In contrast, only 49 microRNAs were altered by FV3 infection, fewer of which were predicted to interact with antiviral pathways. Interestingly, poly(I:C) treatment or FV3 infection downregulated transcripts encoding factors of the host microRNA biogenesis pathway. Our study is the first to suggest that host microRNAs regulate innate antiviral immunity in frogs, and sheds light on microRNA–mediated mechanisms of immunoevasion by FV3.

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A Structural Basis for the Assembly and Functions of a Viral Polymer that Inactivates Multiple Tumor Suppressors

Cell ◽

10.1016/j.cell.2012.08.035 ◽

2012 ◽

Vol 151 (2) ◽

pp. 304-319 ◽

Cited By ~ 54

Author(s):

Horng D. Ou ◽

Witek Kwiatkowski ◽

Thomas J. Deerinck ◽

Andrew Noske ◽

Katie Y. Blain ◽

...

Keyword(s):

Tumor Suppressors ◽

Structural Basis ◽

Multiple Tumor

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Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity

Immunity ◽

10.1016/j.immuni.2012.04.011 ◽

2012 ◽

Vol 37 (1) ◽

pp. 158-170 ◽

Cited By ~ 471

Author(s):

Michael C. Abt ◽

Lisa C. Osborne ◽

Laurel A. Monticelli ◽

Travis A. Doering ◽

Theresa Alenghat ◽

...

Keyword(s):

Antiviral Immunity ◽

Commensal Bacteria ◽

Activation Threshold ◽

Innate Antiviral Immunity

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Mitosis-specific phosphorylation of the nuclear oncoproteins Myc and Myb.

The Journal of Cell Biology ◽

10.1083/jcb.118.4.775 ◽

1992 ◽

Vol 118 (4) ◽

pp. 775-784 ◽

Cited By ~ 57

Author(s):

B Lüscher ◽

R N Eisenman

Keyword(s):

Transcriptional Regulation ◽

Dna Binding ◽

Nuclear Dna ◽

Binding Capacity ◽

Dna Binding Proteins ◽

Response Element ◽

Double Stranded Dna ◽

M Phase ◽

Myb Proteins

The c-myc and c-myb proto-oncogenes encode phosphorylated nuclear DNA binding proteins that are likely to be involved in transcriptional regulation. Here we demonstrate that both Myc and Myb proteins are hyperphosphorylated during mitosis. In the case of Myb, hyperphosphorylation is accompanied by the appearance of three M phase-specific tryptic phosphopeptides. At least one of these phosphopeptides corresponds to a phosphopeptide generated after phosphorylation of Myb in vitro by p34cdc2 kinase. By contrast, the mitotic hyperphosphorylation of Myc does not correlate with the appearance of unique phosphopeptides, suggesting that M phase and interphase sites may be clustered within the same peptides. In addition Myc does not appear to be a target for p34cdc2 phosphorylation. The hyperphosphorylated forms of Myc and Myb from mitotic cells are functionally distinct from the corresponding interphase proteins in that the former have reduced ability to bind nonspecificially to double-stranded DNA cellulose. Furthermore, mitotic Myb binds poorly to oligodeoxynucleotides containing an Myb response element. We surmise that the decreased DNA binding capacity of hyperphosphorylated Myb and Myc during M phase may function to release these proteins from chromatin during chromosome condensation.

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