A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA

Choi, Myoung Kwon; Wang, Zhichao; Ban, Tomohiro; Yanai, Hideyuki; Lu, Yan; Koshiba, Ryuji; Nakaima, Yukana; Hangai, Sho; Savitsky, David; Nakasato, Makoto; Negishi, Hideo; Takeuchi, Osamu; Honda, Kenya; Akira, Shizuo; Tamura, Tomohide; Taniguchi, Tadatsugu

doi:10.1073/pnas.0909545106

Cited by 100 publications

(82 citation statements)

References 33 publications

(49 reference statements)

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“…RIG-I recognizes a wide variety of RNA viruses, whereas MDA5 recognizes mainly picornaviruses whose RNAs do not bear 59-triphosphates (32,37). Intriguingly, several recent studies have revealed that RIG-I and MDA5 are able to induce an antiviral response to viruses containing dsDNA genomes, such as EBV (52,53), vaccinia virus (51, 54), and HSV (55,56). RIG-I is proposed to induce an antiviral response to DNA viruses via RNA poly- merase III-mediated conversion of microbial DNA into 59-triphosphate dsRNA (57,58).…”

Section: Discussionmentioning

confidence: 99%

“…RIG-I is proposed to induce an antiviral response to DNA viruses via RNA poly- merase III-mediated conversion of microbial DNA into 59-triphosphate dsRNA (57,58). Recognition of the DNAs of HSV and EBV by RIG-I is mediated via this pathway (52,55,58). Of note, one report showed that innate recognition of HSV in macrophages is mediated via an MDA5-dependent and RNA polymerase III-independent pathway (56).…”

Section: Discussionmentioning

confidence: 99%

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Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Lu¹,

Liao

2013

The Journal of Immunology

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Retinoic acid–inducible gene-I (RIG-I) and melanoma differentiation–associated gene 5 (MDA5) belong to the RIG-I–like receptors family of pattern recognition receptors. Both RIG-I and MDA5 have been shown to recognize various viral RNAs, but whether they mediate hepatitis B virus (HBV) infection remains unclear. In this study, we demonstrated that the expression of MDA5, but not RIG-I, was increased in Huh7 cells transfected with the HBV replicative plasmid and in the livers of mice hydrodynamically injected with the HBV replicative plasmid. To further determine the effect of RIG-I–like receptors on HBV replication, we cotransfected the HBV replicative plasmid with RIG-I or MDA5 expression plasmid into Huh7 cells and found that MDA5, but not RIG-I at a similar protein level, significantly inhibited HBV replication. Knockdown of endogenous MDA5, but not RIG-I, in Huh7 cells transfected with the HBV replicative plasmid significantly increased HBV replication. Of particular interest, we found that MDA5, but not RIG-I, was able to associate with HBV-specific nucleic acids, suggesting that MDA5 may sense HBV. Finally, we performed in vivo experiments by hydrodynamic injection of the HBV replicative plasmid into wild-type, MDA5−/−, MDA5+/−, or RIG-I+/− mice, and found that MDA5−/− and MDA5+/− mice, but not RIG-I+/− mice, exhibited an increase of HBV replication as compared with wild-type mice. Collectively, our in vitro and in vivo studies both support a critical role for MDA5 in the innate immune response against HBV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Lu¹,

Liao

2013

The Journal of Immunology

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“…During microbial infection or tissue damage, DNA and RNA potently activate the innate and subsequent adaptive immune responses. In mammals, the transmembrane PRR Toll-like receptor (TLR)3, TLR7, and TLR9, respectively, recognize double-stranded RNA, single-stranded and short double-stranded RNAs, and hypomethylated DNA, whereas retinoic acid-inducible gene I (RIG-I)-like receptors, namely RIG-I and melanoma differentiation-associated gene 5 (MDA5), are best known as RNA-sensing receptors in the cytosol, but more recently have been shown to also participate in the cytosolic DNA-sensing system (5)(6)(7)(8). In addition, cytosolic DNA-sensing receptors, which include DNA-dependent activator of IFN regulatory factors (IRFs) (DAI), absent in melanoma 2 (AIM2), among others, have been identified (9, 10).…”

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confidence: 99%

Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with high affinity for high-mobility group box proteins (HMGBs)

Yanai

Chiba

Ban

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The activation of innate immune responses by nucleic acids is central to the generation of host responses against pathogens; however, nucleic acids can also trigger the development and/or exacerbation of pathogenic responses such as autoimmunity. We previously demonstrated that the selective activation of nucleic acid-sensing cytosolic and Toll-like receptors is contingent on the promiscuous sensing of nucleic acids by high-mobility group box proteins (HMGBs). From this, we reasoned that nonimmunogenic nucleotides with high-affinity HMGB binding may function as suppressing agents for HMGB-mediated diseases, particularly those initiated and/or exacerbated by nucleic acids. Here we characterize an array of HMGB-binding, nonimmunogenic oligodeoxynucleotides (niODNs). Interestingly, we find that binding affinity is rather independent of nucleotide sequence, but is instead dependent on length and structure of the deoxyribose backbone. We further show that these ni-ODNs can strongly suppress the activation of innate immune responses induced by both classes of nucleic acid-sensing receptors. We also provide evidence for the suppressive effect of an ni-ODN, termed ISM ODN, on the induction of adaptive immune responses and in mouse models of sepsis and autoimmunity. We discuss our findings in relation to the critical role of HMGBs in initiating immune responses and the possible use of these ni-ODNs in therapeutic interventions.

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“…The reduced IFN- level in Sting -/-MEFs to synthetic poly(dA:dT) dsDNA was accounted for an additional Type I IFN response that is independent of both TLR and STING, and mediated by the dsDNA induced innate immune signalling receptor RIG-1 [60]. RIG-1, a member of the RLR family, is a dsRNA receptor that also triggers antiviral response to dsDNA [186][187][188] . …”

Section: Stingmentioning

confidence: 99%

Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle

Pálmai-Pallag

Bachrati

2014

Microbes and Infection

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Inflammation is the ultimate response to the constant challenges of the immune system by microbes, irritants or injury. The inflammatory cascade initiates with the recognition of microorganism-derived pathogen associated molecular patterns (PAMPs) and host cell-derived damage associated molecular patterns (DAMPs) by the pattern recognition receptors (PRRs). DNA as a molecular PAMP or DAMP is sensed directly or via specific binding proteins to instigate proinflammatory response. Some of these DNA binding proteins also participate in canonical DNA repair pathways and recognise damaged DNA to initiate DNA damage response. In this review we aim to capture the essence of the complex interplay between DNA damage response and the proinflammatory signalling through representative examples. Aetiology and molecular consequences of inflammationInflammation, from the latin inflammare: set on fire, in mammals is the natural defence mechanism of the immune system in response to the constant challenges it is exposed to including injury, toxins and microorganisms, low level cosmic or medical quality radiations (X-ray, -irradiation or UVA/B), drugs and air pollutants (e.g. asbestos or cigarette smoke) 1,2 *. Inflammation is a hallmark of aging and many chronic diseases such as obesity, Chron's disease, Parkinson's disease and autoimmune diseases just to name a few [3][4][5][6][7] . *Additional on-line references are marked by superscript numbers 3The first phase of a complex defence mechanism is acute inflammation instigated by the infiltrated peripheral polymorphonuclear leukocytes (neutrophils), granulocytes (eosinophils) and tissue resident phagocytes (macrophages) at the site of insult. The pro-inflammatory signal is transmitted through the PRRs that can identify danger through DAMPs (e.g. ROS, circulating DNA fragments), cytokines or chemokines released by the damaged tissue or PAMPs from pathogens [1] 8 . The initial role of these cells is to remove the invading pathogen and initiate tissue repair 9 .One of the major defence mechanisms of the activated neutrophils and macrophages is the production of a vast spectrum of endogenous reactive oxygen (ROS) and nitrogen (RNS) species 10 in a process termed "respiratory burst" 11 (see below). However, ROS, as well as the more stable and less reactive by-product of ROS production, hydrogen-peroxide (H 2 O 2 ), are more than toxic products of respiratory burst, they are also effectors for a plethora of signalling pathways inducing innate and adaptive immune cell recruitment, proliferation, tissue healing, cell survival or apoptosis [12][13][14] . Generation of inflammation-induced ROS and RNS mtDNA damageThe circular mtDNA constitutes 1% of total cellular DNA, is of symbiotic bacterial origin, and compared to nuDNA has a very different molecular organisation and regulation. mtDNA has no histones and the methylation of CpG repeat motifs is under-represented, therefore it is particularly vulnerable to damage by endogenous ROS generated by the oxidative electron transpor...

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A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA

Cited by 100 publications

References 33 publications

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with high affinity for high-mobility group box proteins (HMGBs)

Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle

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