MDA-5 Recognition of a Murine Norovirus

McCartney, Stephen A.; Thackray, Larissa B.; Gitlin, Leonid; Gilfillan, Susan; Virgin, Herbert W.; Colonna, Marco

doi:10.1371/journal.ppat.1000108

Cited by 206 publications

(201 citation statements)

References 51 publications

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“…Listeria monocytogenes actively secretes small RNAs via a SecA2 secretion system, thereby triggering strong RIG-I activation that leads to type I IFN production (Abdullah et al 2012;Hagmann et al 2013). Compared with RIG-I, MDA5 recognizes a different class of viruses, such as Picornaviridae, and MDA5-deficient mice show abrogated type I IFN production in response to EMCV, Theiler's virus, hepatitis C virus, mengovirus, and murine norovirus McCartney et al 2008). Moreover, dengue virus, WNV, and reovirus are recognized by both RIG-I and MDA5 in concert (Fredericksen et al 2008;Loo et al 2008).…”

Section: Microbial Sensing and Signalingmentioning

confidence: 99%

Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors

Pandey

Kawai

Akira

2014

Cold Spring Harb Perspect Biol

301

314

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Section: Microbial Sensing and Signalingmentioning

confidence: 99%

Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors

Pandey

Kawai

Akira

2014

Cold Spring Harb Perspect Biol

301

314

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“…123 In dendritic cells, the cytoplasmic helicase protein MDA5 (melanomadifferentiation-associated gene 5) has been demonstrated to be important in cell sensing of the virus. 83 Resistance to infection with MNV1 has been found to rely on the transcription factor STAT-1 and interferon (IFN)-ab receptors for resistance to infection. Thus, Stat1 and Ifra1 (IFNabR) mutant mice will develop clinical disease and death after infection with MNV-1, characterized by severe pneumonia, vasculitis, meningoencephalitis, hepatitis/necrosis, peritonitis, and pleuritis.…”

Section: Viral Agentsmentioning

confidence: 99%

Of Mice and Microflora

et al. 2011

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The phenotype of genetically engineered mice is a combination of both genetic and environmental factors that include the microflora of the mouse. The impact a particular microbe has on a mouse reflects the host-microbe interaction within the context of the mouse genotype and environment. Although often considered a confounding variable, many host-microbe interactions have resulted in the generation of novel model systems and characterization of new microbial agents. Microbes associated with overt disease in mice have been the historical focus of the laboratory animal medical and pathology community and literature. The advent of genetic engineering and the complex of mouse models have revealed previously unknown or disregarded agents that now oblige the attention of the biomedical research community. The purpose of this article is to describe and illustrate how phenotypes can be affected by microflora by focusing on the infectious diseases present in genetically engineered mouse (GEM) colonies of our collective institutions and by reviewing important agents that are rarely seen in most research facilities today. The goal is to introduce the concept of the role of microflora on phenotypes and in translational research using GEM models.

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“…RIG-I detects a variety of positive and negative strand viruses through recognition of a 5′ triphosphate group and blunt ends of genomic RNAs (3, 5, 6). By contrast, MDA5 detects several positive strand and dsRNA viruses such as picornaviruses and reoviruses through recognition of dsRNA replication intermediates and genomic dsRNAs (3,4,7). This viral RNA recognition by MDA5 is independent of 5′ triphosphate or blunt end, but instead depends on dsRNA length in a range of approximately 1-7 kb (8).…”

mentioning

confidence: 99%

Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition

Peisley

Lin

et al. 2011

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

259

310

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MDA5, an RIG-I-like helicase, is a conserved cytoplasmic viral RNA sensor, which recognizes dsRNA from a wide-range of viruses in a length-dependent manner. It has been proposed that MDA5 forms higher-order structures upon viral dsRNA recognition or during antiviral signaling, however the organization and nature of this proposed oligomeric state is unknown. We report here that MDA5 cooperatively assembles into a filamentous oligomer composed of a repeating segmental arrangement of MDA5 dimers along the length of dsRNA. Binding of MDA5 to dsRNA stimulates its ATP hydrolysis activity with little coordination between neighboring molecules within a filament. Individual ATP hydrolysis in turn renders an intrinsic kinetic instability to the MDA5 filament, triggering dissociation of MDA5 from dsRNA at a rate inversely proportional to the filament length. These results suggest a previously unrecognized role of ATP hydrolysis in control of filament assembly and disassembly processes, thereby autoregulating the interaction of MDA5 with dsRNA, and provides a potential basis for dsRNA length-dependent antiviral signaling. (1). Upon viral RNA recognition, RIG-I and MDA5 interact with a common signaling adaptor, MAVS and activate NF-kB and IRF3/7 signaling pathways, resulting in the expression of type I interferon and proinflammatory cytokines (2).Previous studies suggested that RIG-I and MDA5 recognize largely distinct groups of viruses through their divergent RNA specificity (3, 4). RIG-I detects a variety of positive and negative strand viruses through recognition of a 5′ triphosphate group and blunt ends of genomic RNAs (3, 5, 6). By contrast, MDA5 detects several positive strand and dsRNA viruses such as picornaviruses and reoviruses through recognition of dsRNA replication intermediates and genomic dsRNAs (3,4,7). This viral RNA recognition by MDA5 is independent of 5′ triphosphate or blunt end, but instead depends on dsRNA length in a range of approximately 1-7 kb (8).The precise mechanism for length-dependent dsRNA recognition by MDA5 is poorly understood. Previous studies suggest that ATP hydrolysis could play an important role in both interferon signaling and RNA specificity (1, 2). The current model of MDA5 (or RIG-I) mediated signal activation is that binding of viral RNA to MDA5 triggers ATP hydrolysis in the conserved helicase domain, which then alters the receptor conformations or accessibility of the signaling domain (a tandem caspase activation recruitment domain) to allow its interaction with MAVS (1, 9). The proposed role of ATP hydrolysis as a conformational switch for signaling is supported by the requirement of ATP in the reconstituted signaling system of RIG-I (9, 10) and the observation that mutations in the active site for ATP hydrolysis either constitutively activate or inactivate interferon signaling by 12). In addition, induction of ATP hydrolysis by dsRNA has been shown to correlate with stimulation of interferon signaling (6, 13).It has been proposed that MDA5 (and RIG-I) forms a higher-order st...

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MDA-5 Recognition of a Murine Norovirus

Cited by 206 publications

References 51 publications

Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors

Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors

Of Mice and Microflora

Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition

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