Molecular Mechanism of Signal Perception and Integration by the Innate Immune Sensor Retinoic Acid-inducible Gene-I (RIG-I)

Binder, Marco; Eberle, Florian; Seitz, Stefan; Mücke, Norbert; Huber, Carina; Kiani, Narsis A.; Kaderali, Lars; Lohmann, Volker; Dalpke, Alexander H.; Bartenschlager, Ralf

doi:10.1074/jbc.m111.256974

Cited by 119 publications

(138 citation statements)

References 36 publications

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“…Indeed, RNase footprinting of RIG-I/dsRNA complexes showed that the minimum length of RNA protected by RIG-I is 10-15 bp, consistent with both the cocrystal structures and the functional titration and microscopy experiments (Binder et al 2011). Multiple copies of RIG-I can thus bind to dsRNA depending on its length.…”

Section: Rig-i Multimerization and Signalingsupporting

confidence: 48%

“…This suggests that the higher affinity and significantly longer off-rate of 59ppp bpRNA to the CTD, as compared with 59OH bpRNA or 59p bpRNA (Lu et al 2010;Wang et al 2010), is sufficient to discriminate active and inactive ligands. It has also been reported that much longer dsRNAs (>200 bp), including poly(I:C), not necessarily bearing a 59ppp-end or even being blunt-ended, can also induce IFN via RIG-I (Strahle et al 2007;Kato et al 2008;Binder et al 2011). This is more difficult to explain from a structural and biochemical point of view because of the much lower intrinsic affinity of RIG-I for such RNAs.…”

Section: Dsrna and Its 59ppp-ends As Viral Pampsmentioning

confidence: 73%

“…The new RIG-I RNA cocrystal structures are consistent with this (see below). However, in some studies (Lu et al 2010) but not others (Marq et al 2010;Binder et al 2011), it was reported that short, blunt-ended 59OH bpRNAs are also active; this discrepancy may partly be explained by the stability of various transfected 59OH bpRNAs within different cells. On the other hand, some bunyavirus genomes appear to escape RIG-I detection because they contain blunt-ended dsRNA panhandles that contain only 59 monophosphates (Habjan et al 2008).…”

Section: Dsrna and Its 59ppp-ends As Viral Pampsmentioning

confidence: 99%

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A structure-based model of RIG-I activation

Kolakofsky

Kowalinski

Cusack

2012

RNA

137

134

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Section: Rig-i Multimerization and Signalingsupporting

confidence: 48%

Section: Dsrna and Its 59ppp-ends As Viral Pampsmentioning

confidence: 73%

Section: Dsrna and Its 59ppp-ends As Viral Pampsmentioning

confidence: 99%

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A structure-based model of RIG-I activation

Kolakofsky

Kowalinski

Cusack

2012

RNA

137

134

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“…Binder et al [27] showed some evidence of RIG-I oligomerization on dsRNA by scanning force microscopy and size-exclusion chromatography. However, the role of 5 0 -ppp on RNA was not tested and the experiments were performed in the absence of ATP, which is an essential co-factor for activation.…”

Section: Resultsmentioning

confidence: 99%

ATPase‐driven oligomerization of RIG‐I on RNA allows optimal activation of type‐I interferon

et al. 2013

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The cytosolic pathogen sensor RIG-I is activated by RNAs with exposed 5 0 -triphosphate (5 0 -ppp) and terminal double-stranded structures, such as those that are generated during viral infection. RIG-I has been shown to translocate on dsRNA in an ATPdependent manner. However, the precise role of the ATPase activity in RIG-I activation remains unclear. Using in vitrotranscribed Sendai virus defective interfering RNA as a model ligand, we show that RIG-I oligomerizes on 5 0 -ppp dsRNA in an ATP hydrolysis-dependent and dsRNA length-dependent manner, which correlates with the strength of type-I interferon (IFN-I) activation. These results establish a clear role for the ligand-induced ATPase activity of RIG-I in the stimulation of the IFN response.

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“…It has been proposed that MDA5 (and RIG-I) forms a higher-order structure during viral RNA recognition for efficient antiviral signaling (14)(15)(16). Receptor oligomerization or clustering, as demonstrated in other receptors, such as inflammasomes, Toll-like receptors, T-and B-cell receptors, is often important for ligand sensitivity and downstream signaling efficiency (17,18).…”

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.

267

312

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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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Molecular Mechanism of Signal Perception and Integration by the Innate Immune Sensor Retinoic Acid-inducible Gene-I (RIG-I)

Cited by 119 publications

References 36 publications

A structure-based model of RIG-I activation

A structure-based model of RIG-I activation

ATPase‐driven oligomerization of RIG‐I on RNA allows optimal activation of type‐I interferon

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

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