MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response

Hou, Fanfan; Sun, Lijun; Zheng, Hui; Skaug, Brian; Jiang, Qiu Xing; Chen, Zhijian J.

doi:10.1016/j.cell.2011.06.041

Cited by 1,070 publications

(1,119 citation statements)

References 38 publications

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“…As many receptors in the immune system cluster for effective signal transmission (17,18), clustering of MDA5 on dsRNA may facilitate recruitment of MAVS or subsequent oligomerization of MAVS, which itself was recently shown to form prion-like fibrillar structures during antiviral signaling (10). It has been proposed that recruitment of MAVS by MDA5 depends on a conformational change of MDA5 induced by ATP hydrolysis (1,10). It would be interesting to test whether ATP hydrolysis by individual MDA5 molecules within a filament recruits MAVS and promote their oligomerization through induced proximity.…”

Section: Discussionmentioning

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.

268

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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Section: Discussionmentioning

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.

268

312

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“…It has been shown that the intact tandem CARDs are essential and sufficient for signaling [9,36,37], and mammalian RIG-I mutants with a CARD deletion or CARD point mutations (T55I or S183I) all function as a dominant inhibitor in its signaling [9,11,38]. It has also been revealed in mammals that the RIG-I downstream signaling via MAVS requires the recruitment of TRIM25 and other ubiquitination enzymes to synthesize unanchored K63-linked polyubiquitin chains binding to the CARD domains [36,37,39,40]. In the present study, RIG-Ia, the insertion variant of RIG-I with additional 38-aa residues in the CARD2 domain had no direct role in the activation of type I IFN promoter or antiviral defense, although the expression level of RIG-Ia could be induced under E. tarda or SVCV infections.…”

Section: Discussionmentioning

confidence: 99%

Higher antiviral response of RIG-I through enhancing RIG-I/MAVS-mediated signaling by its long insertion variant in zebrafish

Zou

Chang

et al. 2015

Fish & Shellfish Immunology

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“…Hou et al have now used this powerful in vitro system to make the remarkable discovery that MAVS forms prion-like aggregates to propagate RIG-I signaling [7]. They mixed recombinant RIG-I, mitochondria, 5′-pppRNA, ATP, and K63 ubiquitin chains (K63-Ub4), or isolated mitochondria from cells infected with Sendai virus.…”

mentioning

confidence: 99%

Prion-like behavior of MAVS in RIG-I signaling

2011

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MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response

Cited by 1,070 publications

References 38 publications

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

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

Higher antiviral response of RIG-I through enhancing RIG-I/MAVS-mediated signaling by its long insertion variant in zebrafish

Prion-like behavior of MAVS in RIG-I signaling

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