IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes

Almine, Jessica F.; O'Hare, Craig; Dunphy, Gillian; Haga, Ismar R.; Naik, Rangeetha J.; Atrih, Abdelmadjid; Connolly, Dympna J.; Taylor, Jordan S.; Kelsall, Ian R.; Bowie, Andrew; Beard, Philippa M.; Unterholzner, Leonie

doi:10.1038/ncomms14392

Cited by 266 publications

(250 citation statements)

References 53 publications

(98 reference statements)

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“…5R), suggesting that both sensors are functionally involved in recognition of ALVAC. This result is consistent with recent studies showing that cGAS and IFI16 cooperate to sense intracellular viral DNAs together (40, 41). Collectively, using a combination of antibody blockade and gene-editing approaches, we demonstrate that ALVAC stimulates cGAS/IFI16-STING-Type I IFN pathway, leading to priming of AIM2 for subsequent inflammasome activation by ALVAC.…”

Section: Resultssupporting

confidence: 93%

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Liu

Niu

Fan

et al. 2017

The Journal of Immunology

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Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about mechanisms underlying host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of antigen presenting cells (APCs) with two commonly used HIV vaccine vectors, ALVAC and Ad5, and herein reported identification of AIM2 as an innate sensor for ALVAC triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16-STING-Type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that different from ALVAC, Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate STING-Type I IFN pathway and to provide inflammasome priming signals. In pre-conditioned APCs, Ad5 vector could stimulate inflammasome activation through AIM2-independent mechanism. Therefore, our study identifies AIM2 inflammasome and cGAS/IFI16-STING-Type I IFN pathway as novel mechanism for host innate immunity to ALVAC vaccine vector.

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Section: Resultssupporting

confidence: 93%

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Liu

Niu

Fan

et al. 2017

The Journal of Immunology

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“…iRhom2 is essential for STING to traffic from the ER to the Golgi, and iRhom2 deficient cells lose the ability to form perinuclear endosomes containing STING following viral infection or DNA transfection . In addition to promoting cGAS activation, the DNA sensor IFI16 actively recruits TBK1 to STING . The IFN‐inducible gene IFIT3 also has been reported to promote STING‐TBK1 binding, and SCAP is a scaffold adaptor that travels with STING and recruits IRF3 to the complex with TBK1 .…”

Section: Basic Biology Of the Sting Pathwaymentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

235

183

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The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

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“…Additionally, STING is also regulated by trafficking to ERGIC and degradation through autophagy by Golgi and p62/SQSTM1 72. Furthermore, cGAMP‐induced activation of STING requires IFI16 for antiviral defense and is regulated by various viral proteins 85. Additionally, IFI16 is inhibited by human cytomegalovirus (HCMV) tegument protein pUL83, which results in immune evasion 86.…”

Section: Regulation Of Innate Immune Responsesmentioning

confidence: 99%

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

et al. 2020

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Early detection of infectious nucleic acids released from invading pathogens by the innate immune system is critical for immune defense. Detection of these nucleic acids by host immune sensors and regulation of DNA sensing pathways have been significant interests in the past years. Here, current understandings of evolutionarily conserved DNA sensing cyclic GMP‐AMP (cGAMP) synthase (cGAS) are highlighted. Precise activation and tight regulation of cGAS are vital in appropriate innate immune responses, senescence, tumorigenesis and immunotherapy, and autoimmunity. Hence, substantial insights into cytosolic DNA sensing and immunotherapy of indispensable cytosolic sensors have been detailed to extend limited knowledge available thus far. This Review offers a critical, in‐depth understanding of cGAS regulation, cytosolic DNA sensing, and currently established therapeutic approaches of essential cytosolic immune agents for improved human health.

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IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes

Cited by 266 publications

References 53 publications

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

STING pathway agonism as a cancer therapeutic

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

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