Human DNA-PK activates a STING-independent DNA sensing pathway

Burleigh, Katelyn; Maltbaek, Joanna H.; Cambier, Stephanie; Green, Richard; Gale, Michael; James, Richard G.; Stetson, Daniel B.

doi:10.1126/sciimmunol.aba4219

Cited by 127 publications

(124 citation statements)

References 120 publications

(185 reference statements)

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“…Recent studies show the existence of a parallel DNA-PK-dependent, but cGAS-STING-independent DNA sensing pathway in humans but not in mice. 151 Whether the AIM2 inflammasome has any regulatory effect on this new DNA sensing pathway is not known. Although the differential expression of AIM2 is associated with various sterile inflammatory diseases and cancers, the roles of AIM2 in these disease conditions remain largely unknown.…”

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

AIM2 in health and disease: Inflammasome and beyond

Kumari

Russo

Shivcharan

et al. 2020

Immunological Reviews

119

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Nucleic acid sensing is a critical mechanism by which the immune system monitors for pathogen invasion. A set of germline‐encoded innate immune receptors detect microbial DNA in various compartments of the cell, such as endosomes, the cytosol, and the nucleus. Sensing of microbial DNA through these receptors stimulates, in most cases, interferon regulatory factor‐dependent type I IFN synthesis followed by JAK/STAT‐dependent interferon‐stimulated gene expression. In contrast, the detection of DNA in the cytosol by AIM2 assembles a macromolecular complex called the inflammasome, which unleashes the proteolytic activity of a cysteine protease caspase‐1. Caspase‐1 cleaves and activates the pro‐inflammatory cytokines such as IL‐1β and IL‐18 and a pore‐forming protein, gasdermin D, which triggers pyroptosis, an inflammatory form of cell death. Research over the past decade has revealed that AIM2 plays essential roles not only in host defense against pathogens but also in inflammatory diseases, autoimmunity, and cancer in inflammasome‐dependent and inflammasome‐independent manners. This review discusses the latest advancements in our understanding of AIM2 biology and its functions in health and disease.

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Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

AIM2 in health and disease: Inflammasome and beyond

Kumari

Russo

Shivcharan

et al. 2020

Immunological Reviews

119

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“…Two of these molecules, IFI16 and DNA-PK, have been reported to have direct roles in VACV sensing and are discussed below in more detail. One of them, namely DNA-PK, has been recently implicated in STING-independent IFN-I production in response to DNA and involves the downstream signaling of the heat shock protein HSPA8, in what is being referred to as the STING-independent DNA sensing pathway (SIDSP) (93).…”

Section: Overview Of Antiviral Cytosolic Dna Sensingmentioning

confidence: 99%

Vaccinia Virus Activation and Antagonism of Cytosolic DNA Sensing

2020

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Cells express multiple molecules aimed at detecting incoming virus and infection. Recognition of virus infection leads to the production of cytokines, chemokines and restriction factors that limit virus replication and activate an adaptive immune response offering long-term protection. Recognition of cytosolic DNA has become a central immune sensing mechanism involved in infection, autoinflammation, and cancer immunotherapy. Vaccinia virus (VACV) is the prototypic member of the family Poxviridae and the vaccine used to eradicate smallpox. VACV harbors enormous potential as a vaccine vector and several attenuated strains are currently being developed against infectious diseases. In addition, VACV has emerged as a popular oncolytic agent due to its cytotoxic capacity even in hypoxic environments. As a poxvirus, VACV is an unusual virus that replicates its large DNA genome exclusively in the cytoplasm of infected cells. Despite producing large amounts of cytosolic DNA, VACV efficiently suppresses the subsequent innate immune response by deploying an arsenal of proteins with capacity to disable host antiviral signaling, some of which specifically target cytosolic DNA sensing pathways. Some of these strategies are conserved amongst orthopoxviruses, whereas others are seemingly unique to VACV. In this review we provide an overview of the VACV replicative cycle and discuss the recent advances on our understanding of how VACV induces and antagonizes innate immune activation via cytosolic DNA sensing pathways. The implications of these findings in the rational design of vaccines and oncolytics based on VACV are also discussed.

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“…107,108 Nevertheless, DDR sensors such as DNA-dependent protein kinase (DNA-PK) and meiotic recombination 11 homolog A (MRE11) have also been reported to recognize viral genomic DNA and induce innate immune responses as innate immune sensors. [109][110][111] Of note, DNA-PK is found to specifically sense transfected calf thymus (CT) DNA in human cells rather than mouse cells. Especially, unlike IFI16 and hnRNPA2B1, the activated DNA-PK induces IFNs production in a STING-independent DNA sensing pathway (SIDSP), which requires phosphorylated heat shock protein HSPA8 and IRF3.…”

Section: Per S Pec Tive and Future Direc Tionsmentioning

confidence: 99%

“…Especially, unlike IFI16 and hnRNPA2B1, the activated DNA-PK induces IFNs production in a STING-independent DNA sensing pathway (SIDSP), which requires phosphorylated heat shock protein HSPA8 and IRF3. 110 HSV-1 protein ICP0 mediates the polyubiquitination and degradation of DNA-PK, thus inhibiting the phosphorylation of HSPA8 and antiviral immune response. 110,112,113 However, these studies have not shown that the DDR sensors detect viral DNA in the nucleus or clearly indicated the specific locations of these viral DNA sensors.…”

Section: Per S Pec Tive and Future Direc Tionsmentioning

confidence: 99%

Nuclear innate sensors for nucleic acids in immunity and inflammation

Lin

Cao

2020

Immunological Reviews

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Innate sensors recognize pathogen‐associated molecular patterns (PAMPs) or damage‐associated molecular patterns (DAMPs) to initiate innate immune response by activating downstream signaling. These evolutionarily conserved innate sensors usually locate in the plasma membrane or cytoplasm. However, the nucleus‐localized innate sensors are recently found to detect pathogenic nucleic acids for initiating innate response, demonstrating a complicated crosstalk with cytoplasmic sensors and signaling molecules to form an elaborate tiered innate signaling network between nucleus and cytoplasm. Furthermore, these nuclear innate sensors evolve varied mechanisms for discriminating self from non‐self nucleic acids to maintain immune homeostasis and avoid autoinflammatory immune response. In this review, we summarize the recent findings on the identification of nuclear innate sensors for nucleic acids, such as hnRNPA2B1, IFI16, SAFA, and their roles in host defense and inflammatory response.

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Human DNA-PK activates a STING-independent DNA sensing pathway

Cited by 127 publications

References 120 publications

AIM2 in health and disease: Inflammasome and beyond

AIM2 in health and disease: Inflammasome and beyond

Vaccinia Virus Activation and Antagonism of Cytosolic DNA Sensing

Nuclear innate sensors for nucleic acids in immunity and inflammation

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