Structural Basis for the Prion-Like Mavs Filaments in Antiviral Innate Immunity

eLife Sciences (Impact Factor: 9.32). 02/2014; 3(2):e01489. DOI: 10.7554/eLife.01489
Source: PubMed


Mitochondrial antiviral signaling (MAVS) protein is required for innate immune responses against RNA viruses. In virus-infected cells MAVS forms prion-like aggregates to activate antiviral signaling cascades, but the underlying structural mechanism is unknown. Here we report cryo-electron microscopic structures of the helical filaments formed by both the N-terminal caspase activation and recruitment domain (CARD) of MAVS and a truncated MAVS lacking part of the proline-rich region and the C-terminal transmembrane domain. Both structures are left-handed three-stranded helical filaments, revealing specific interfaces between individual CARD subunits that are dictated by electrostatic interactions between neighboring strands and hydrophobic interactions within each strand. Point mutations at multiple locations of these two interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed rod-shaped MAVS clusters on mitochondria. These results elucidate the structural mechanism of MAVS polymerization, and explain how an α-helical domain uses distinct chemical interactions to form self-perpetuating filaments. DOI:

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    • "presented the structures of prion-like MAVS and found there are " electrostatic interactions between neighboring strands and hydrophobic interactions within each strand " [Xu et al. (2014)]. "
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    ABSTRACT: "A Podcast of Social Media Marketing of the Bentham Science Publishers" can be seen at Bentham's websites: (1) (2) (3) (4) (5) Prion diseases which are serious neurodegenerative diseases that affect humans and animals occur in various of species. Unlike many other neurodegenerative diseases affected by amyloid, prion diseases can be highly infectious. Prion diseases occur in many species. In humans, prion diseases include the fatal human neurodegenerative diseases such as Creutzfeldt-Jakob Disease (CJD), Fatal Familial Insomnia (FFI), Gerstmann-Strussler-Scheinker syndrome (GSS) and Kuru etc. In animals, prion diseases are related to the bovine spongiform encephalopathy (BSE or ‘mad-cow’ disease) in cattle, the chronic wasting disease (CWD) found in deer and elk, and scrapie seen in sheep and goats, etc. More seriously, the fact that transmission of the prion diseases across the species barrier to other species such as humans has caused a major public health concern worldwide. For example, the BSE in Europe, the CWD in North America, and variant CJDs (vCJDs) in young people of UK. Fortunately, it is discovered that the hydrophobic region of prion proteins (PrPCs) controls the formation of diseased prions (PrPSc), which provides some clues in control of such diseases. This article provides a detailed survey of recent studies with respect to the PrPC hydrophobic region of human PrP(110–136) using molecular dynamics studies (earliest & 1st version, see:
    Current Pharmaceutical Biotechnology 07/2015; 15(11):pp. 1026-1048. PMID: 25373387. DOI:10.2174/1389201015666141103020004; · 2.51 Impact Factor
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    • "These data in conjunction with previous findings in other studies support the hypothesis that the detrimental effect of PB1-F2 on the host could be mediated by the activated form of MAVS (i.e. filamentous form, [53]). The absence of RIG-I in the chicken genome imply that MAVS is probably less activated during infection and consequently reduce the negative effects of PB1-F2. "
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    ABSTRACT: Highly pathogenic avian influenza virus (HPAIV) is a permanent threat due to its capacity to cross species barriers and generate severe infections and high mortality in humans. Recent findings have highlighted the potential role of PB1-F2, a small accessory influenza protein, in the pathogenesis process mediated by HPAIV in mammals. In this study, using a recombinant H5N1 HPAIV (wt) and its PB1-F2-deleted mutant (ΔF2), we studied the effects of PB1-F2 in a chicken model. Unexpectedly, when using low inoculation dose we observed that the wt-infected chickens had a higher survival rate than the ΔF2-infected chickens, a feature that contrasts with what is usually observed in mammals. High inoculation dose had similar mortality rate for both viruses, and comparison of the bio-distribution of the two viruses indicated that the expression of PB1-F2 allows a better spreading of the virus within chicken embryos. Transcriptomic profiles of lungs and blood cells were characterized at two days post-infection in chickens inoculated with the wild type (wt) or the ΔF2 mutant viruses. In lungs, the expression of PB1-F2 during the infection induced pathways related to calcium signaling and repressed a large panel of immunological functions. In blood cells, PB1-F2 was associated with a gene signature specific for mitochondrial dysfunction and down-modulated leucocytes activation. Finally we compared the effect of PB1-F2 in lungs of chickens and mice. We identified that gene signature associated to tissue damages is a PB1-F2 feature shared by the two species; by contrast, the early inhibition of immune response mediated by PB1-F2 observed in chickens is not seen in mice. In summary, our data suggest that PB1-F2 expression deeply affect the immune response in chickens in a way that may attenuate pathogenicity at low infection dose, a feature differing from what was previously observed in mammal species.
    PLoS ONE 06/2014; 9(6):e100679. DOI:10.1371/journal.pone.0100679 · 3.23 Impact Factor
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    ABSTRACT: Mitochondrial antiviral signalling proteins form an intricate three-stranded helical filament that has a central role in the response of cells to viruses.
    eLife Sciences 03/2014; 3(3):e02369. DOI:10.7554/eLife.02369 · 9.32 Impact Factor
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