Author response: DNA-PK is a DNA sensor for IRF-3-dependent innate immunity

Ferguson, Brian J.; Mansur, Daniel S; Peters, Nicholas E; Ren, Hongwei; Smith, Geoffrey L.

doi:10.7554/elife.00047.012

Cited by 4 publications

(2 citation statements)

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“…For instance, studies showed that DNA damage induced by etoposide or by doxorubicin instigates an ATM-dependent but cGASindependent immune response (Luthra et al, 2017;Dunphy et al, 2018). In addition, DNA-dependent protein kinase (DNA-PK) was characterized as another DNA sensor contributing to IFN-I (Ferguson et al, 2012), and more recently, DNA-PK has been suggested to induce a cGAS-STING-independent IFN-I induction upon DNA damage in humans but not in mice, highlighting species differences in immune activation following DNA breaks (Burleigh et al, 2020). Further, DNA-PK antagonizes cGAS activation through inhibition of its catalytic activity.…”

Section: Cgas Independent Activation Of Ifn-i Responsementioning

confidence: 99%

Type-I Interferon Signaling in Fanconi Anemia

Landelouci

Sinha

Pépin

2022

Front. Cell. Infect. Microbiol.

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Fanconi Anemia (FA) is a genome instability syndrome caused by mutations in one of the 23 repair genes of the Fanconi pathway. This heterogenous disease is usually characterized by congenital abnormalities, premature ageing and bone marrow failure. FA patients also show a high predisposition to hematological and solid cancers. The Fanconi pathway ensures the repair of interstrand crosslinks (ICLs) DNA damage. Defect in one of its proteins prevents functional DNA repair, leading to the accumulation of DNA breaks and genome instability. Accumulating evidence has documented a close relationship between genome instability and inflammation, including the production of type-I Interferon. In this context, type-I Interferon is produced upon activation of pattern recognition receptors by nucleic acids including by the cyclic GMP-AMP synthase (cGAS) that detects DNA. In mouse models of diseases displaying genome instability, type-I Interferon response is responsible for an important part of the pathological symptoms, including premature aging, short stature, and neurodegeneration. This is illustrated in mouse models of Ataxia-telangiectasia and Aicardi-Goutières Syndrome in which genetic depletion of either Interferon Receptor IFNAR, cGAS or STING relieves pathological symptoms. FA is also a genetic instability syndrome with symptoms such as premature aging and predisposition to cancer. In this review we will focus on the different molecular mechanisms potentially leading to type-I Interferon activation. A better understanding of the molecular mechanisms engaging type-I Interferon signaling in FA may ultimately lead to the discovery of new therapeutic targets to rescue the pathological inflammation and premature aging associated with Fanconi Anemia.

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Section: Cgas Independent Activation Of Ifn-i Responsementioning

confidence: 99%

Type-I Interferon Signaling in Fanconi Anemia

Landelouci

Sinha

Pépin

2022

Front. Cell. Infect. Microbiol.

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“…DNA protein kinase (DNA-PK) is a protein complex made up of a DNA protein kinase catalytic subunit (DNA-PKcs), ku70, and ku80, and is best known for its role in DNA double stranded break repair. However, several studies have shown that it can bind to transfected DNA and elicit the expression of IFN-β and other ISGs, independent of kinase activity (Ferguson et al, 2012;Harnor et al, 2017;Burleigh et al, 2020). In addition, the Ku70 subunit has also been identified as a possible DNA sensor in studies where plasmid transfected HEK 293 cells produce the type three IFN, IFN-λ1, that can limit HIV replication (Zhang X. et al, 2011).…”

Section: Ddx41 Ku70/dna-pk and Rna Polymerase IIImentioning

confidence: 99%

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Jeffries

Marriott

2020

Front. Cell. Infect. Microbiol.

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Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood. Recently, a class of intracellular pattern recognition receptors (PRRs), collectively known as DNA sensors, have been identified in both leukocytic and non-leukocytic cell types. The ability of such DNA sensors to initiate immune mediator production and contribute to infection resolution in the periphery is increasingly recognized, but our understanding of their role in the CNS remains limited at best. In this review, we describe the evidence for the expression and functionality of DNA sensors in resident brain cells, with a focus on their role in neurotropic virus infections. The available data indicate that glia and neurons can constitutively express, and/or can be induced to express, various disparate DNA sensing molecules previously described in peripheral cell types. Furthermore, multiple lines of investigation suggest that these sensors are functional in resident CNS cells and are required for innate immune responses to viral infections. However, it is less clear whether DNA sensormediated glial responses are beneficial or detrimental, and the answer to this question appears to dependent on the context of the infection with regard to the identity of the pathogen, host cell type, and host species. Defining such parameters will be essential if we are to successfully target these molecules to limit damaging inflammation while allowing beneficial host responses to improve patient outcomes.

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DNA-Sensing Antiviral Innate Immunity in Poxvirus Infection

Zhang

2020

Front. Immunol.

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As pattern recognition receptors, cytosolic DNA sensors quickly induce an effective innate immune response. Poxvirus, a large DNA virus, is capable of evading the host antiviral innate immune response. In this review, we summarize the latest studies on how poxvirus is sensed by the host innate immune system and how poxvirus-encoded proteins antagonize DNA sensors. A comprehensive understanding of the interplay between poxvirus and DNA-sensing antiviral immune responses of the host will contribute to the development of new antiviral therapies and vaccines in the future.

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Author response: DNA-PK is a DNA sensor for IRF-3-dependent innate immunity

Cited by 4 publications

References 0 publications

Type-I Interferon Signaling in Fanconi Anemia

Type-I Interferon Signaling in Fanconi Anemia

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

DNA-Sensing Antiviral Innate Immunity in Poxvirus Infection

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