Antagonism of the Phosphatase PP1 by the Measles Virus V Protein Is Required for Innate Immune Escape of MDA5

Davis, Meredith E.; Wang, May K.; Rennick, Linda J.; Full, Florian; Gableske, Sebastian; Mesman, Annelies W.; Gringhuis, Sonja I.; Geijtenbeek, Teunis B. H.; Duprex, W. Paul; Gack, Michaela U.

doi:10.1016/j.chom.2014.06.007

Cited by 118 publications

(118 citation statements)

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“…Although the NiV V and W proteins have previously described roles in directly inhibiting type I interferon (IFN) induction and signaling (30,(32)(33)(34)(35)(36)(37), the contribution of the NiV C protein has not been well defined. The NiV C protein appears to decrease viral RNA synthesis (26,38,39), thus indirectly inhibiting type I IFN induction.…”

mentioning

confidence: 99%

Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets

Satterfield

Cross

Fenton

et al. 2016

J Virol

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Nipah virus (NiV) is a highly lethal paramyxovirus that recently emerged as a causative agent of febrile encephalitis and severe respiratory disease in humans. The ferret model has emerged as the preferred small-animal model with which to study NiV disease, but much is still unknown about the viral determinants of NiV pathogenesis, including the contribution of the C protein in ferrets. Additionally, studies have yet to examine the synergistic effects of the various P gene products on pathogenesis in animal models. Using recombinant NiVs (rNiVs), we examine the sole contribution of the NiV C protein and the combined contributions of the C and W proteins in the ferret model of NiV pathogenesis. We show that an rNiV void of C expression resulted in 100% mortality, though with limited respiratory disease, like our previously reported rNiV void of W expression; this finding is in stark contrast to the attenuated phenotype observed in previous hamster studies utilizing rNiVs void of C expression. We also observed that an rNiV void of both C and W expression resulted in limited respiratory disease; however, there was severe neurological disease leading to 60% mortality, and the surviving ferrets demonstrated sequelae similar to those for human survivors of NiV encephalitis. IMPORTANCE Nipah virus (NiV) is a human pathogen capable of causing lethal respiratory and neurological disease. Many human survivors have long-lasting neurological impairment. Using a ferret model, this study demonstrated the roles of the NiV C and W proteinsin pathogenesis, where lack of either the C or the W protein independently decreased the severity of clinical respiratory disease but did not decrease lethality. Abolishing both C and W expression, however, dramatically decreased the severity of respiratory disease and the level of destruction of splenic germinal centers. These ferrets still suffered severe neurological disease: 60% succumbed to disease, and the survivors experienced long-term neurological impairment, such as that seen in human survivors. This new ferret NiV C and W knockout model may allow, for the first time, the examination of interventions to prevent or mitigate the neurological damage and sequelae experienced by human survivors.

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confidence: 99%

Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets

Satterfield

Cross

Fenton

et al. 2016

J Virol

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“…Paramyxoviral V proteins show surprising sophistication in inhibiting virus detection by the sensor MDA5. Not only does V directly bind and inhibit both MDA5 and LGP2, but it also binds the cellular phosphatase PP1, keeping it from dephosphorylating MDA5 and hence maintaining MDA5 in an inactive conformation (153)(154)(155)(156). The prime example of a multifunctional antihost protein is FLUAV NS1.…”

Section: Viral Antagonism Of the Interferon Systemmentioning

confidence: 98%

No Love Lost Between Viruses and Interferons

2015

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The interferon system protects mammals against virus infections. There are several types of interferons, which are characterized by their ability to inhibit virus replication and resultant pathogenesis by triggering both innate and cell-mediated immune responses. Virus infection is sensed by a variety of cellular pattern-recognition receptors and triggers the synthesis of interferons, which are secreted by the infected cells. In uninfected cells, cell surface receptors recognize the secreted interferons and activate intracellular signaling pathways that induce the expression of interferon-stimulated genes; the proteins encoded by these genes inhibit different stages of virus replication. To avoid extinction, almost all viruses have evolved mechanisms to defend themselves against the interferon system. Consequently, a dynamic equilibrium of survival is established between the virus and its host, an equilibrium that can be shifted to the host's favor by the use of exogenous interferon as a therapeutic antiviral agent.

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“…The V proteins from paramyxoviruses Nipah virus (NiV) and measles virus (MeV) can bind to PP1α/γ to inhibit the dephosphorylation of MDA5 at Ser88 [38] (Fig. 5B).…”

Section: Type I Ifn Induction During Viral Infectionmentioning

confidence: 99%

“…The C-terminal tail of MeV V protein contains a consensus PP1-binding motif within residues 288 to 291 consisting of amino acids Arg-Ile-Trp-Tyr-Thr. Deletion of this region results in enhanced dephosphorylation of MDA5 at Ser88 in human dendritic cells and negatively impacts viral propagation in human lung epithelial cells [38]. In vitro experiments further show that PP1 is capable of dephosphorylating MeV V proteins as MeV V is phosphorylated at several locations [39–42], suggesting that MeV V acts as a decoy substrate of PP1 to divert the dephosphorylation of MDA5 [38].…”

Section: Type I Ifn Induction During Viral Infectionmentioning

confidence: 99%

“…Deletion of this region results in enhanced dephosphorylation of MDA5 at Ser88 in human dendritic cells and negatively impacts viral propagation in human lung epithelial cells [38]. In vitro experiments further show that PP1 is capable of dephosphorylating MeV V proteins as MeV V is phosphorylated at several locations [39–42], suggesting that MeV V acts as a decoy substrate of PP1 to divert the dephosphorylation of MDA5 [38]. However, a consensus PP1 binding site is not present in NiV V protein and inhibition of phosphorylation by NiV and MeV V proteins is limited to MDA5 [38].…”

Section: Type I Ifn Induction During Viral Infectionmentioning

confidence: 99%

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Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses

Chatterjee

Basler

Amarasinghe

et al. 2016

Journal of Molecular Biology

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The host innate immune system serves as the first line of defense against viral infections. Germline encoded pattern recognition receptors (PRRs) detect molecular patterns associated with pathogens and activate innate immune responses. Of particular relevance to viral infections are those PRRs that activate type I interferon (IFN) responses, which establish an antiviral state. The Order Mononegavirales is comprised of viruses that possess single-stranded, non-segmented, negative-sense (NNS) RNA genomes and are important human pathogens that consistently antagonize signaling related to IFN responses. NNS viruses (NNSVs) have limited encoding capacity compared to many DNA viruses. And as a likely consequence, most open reading frames (ORFs) encode multifunctional viral proteins that interact with host factors in order to evade host cell defenses while promoting viral replication. In this review, we will discuss the molecular mechanisms of innate immune evasion by select NNSVs. A greater understanding of these interactions will be critical in facilitating the development of effective therapeutics and viral countermeasures.

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Antagonism of the Phosphatase PP1 by the Measles Virus V Protein Is Required for Innate Immune Escape of MDA5

Cited by 118 publications

References 44 publications

Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets

Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets

No Love Lost Between Viruses and Interferons

Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses

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