Interaction of Rabies Virus P-Protein With STAT Proteins is Critical to Lethal Rabies Disease

Wiltzer, Linda; Okada, Kazuma; Yamaoka, Satoko; Larrous, Florence; Kuusisto, Henna Veera; Sugiyama, Makoto; Blondel, Danielle; Bourhy, Hervé; Jans, David A.; Ito, Naoto; Moseley, Gregory W.

doi:10.1093/infdis/jit829

Cited by 71 publications

(136 citation statements)

References 43 publications

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“…Phosphorylated IRF-3 is translocated to the nucleus and activates the transcription of type I IFNs, IFN-a and -b. Secreted type I IFNs bind to a common receptor and activate Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling, which subsequently induces transcription of hundreds of IFN-stimulated genes (ISGs) including antiviral and apoptotic genes (Randall & Goodbourn, 2008;van Boxel-Dezaire et al, 2006). Previous studies reported that the P protein of RABV antagonizes JAK/STAT signalling by interacting with STAT-1, -2 and -3 (Vidy et al, 2005(Vidy et al, , 2007Brzó zka et al, 2006;Ito et al, 2010;Lieu et al, 2013;Wiltzer et al, 2014). In addition, the RABV P protein also interferes with TBK1 and IKKe-mediated IRF-3 activation and consequently inhibits type I IFN induction (Brzó zka et al, 2005;Rieder et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Contribution of the interaction between the rabies virus P protein and I-kappa B kinase ϵ to the inhibition of type I IFN induction signalling

Masatani

Ozawa

Yamada

et al. 2016

Journal of General Virology

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The P protein of rabies virus (RABV) is known to interfere with the phosphorylation of the host IFN regulatory factor 3 (IRF-3) and to consequently inhibit type I IFN induction. Previous studies, however, have only tested P proteins from laboratory-adapted fixed virus strains, and to the best of our knowledge there is no report about the effect of P proteins from street RABV strains or other lyssaviruses on the IRF-3-mediated type I IFN induction system. In this study, we evaluated the inhibitory effect of P proteins from several RABV strains, including fixed and street virus strains and other lyssaviruses (Lagos bat, Mokola and Duvenhage viruses), on IRF-3 signalling. All P proteins tested inhibited retinoic acid-inducible gene-1 (RIG-I)-and TANK binding kinase 1 (TBK1)-mediated IRF-3-dependent IFN-b promoter activities. On the other hand, the P proteins from the RABV street strains 1088 and HCM-9, but not from fixed strains Nishigahara (Ni) and CVS-11 and other lyssaviruses tested, significantly inhibited I-kappa B kinase e (IKKe)-inducible IRF-3-dependent IFN-b promoter activity. Importantly, we revealed that the P proteins from the 1088 and HCM-9 strains, but not from the remaining viruses, interacted with IKKe. By using expression plasmids encoding chimeric P proteins from the 1088 strain and Ni strain, we found that the C-terminal region of the P protein is important for the interaction with IKKe. These findings suggest that the P protein of RABV street strains may contribute to efficient evasion of host innate immunity.

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Section: Introductionmentioning

confidence: 99%

Contribution of the interaction between the rabies virus P protein and I-kappa B kinase ϵ to the inhibition of type I IFN induction signalling

Masatani

Ozawa

Yamada

et al. 2016

Journal of General Virology

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“…Specifically, this protein plays an essential role in viral RNA synthesis as a cofactor of viral RNA-dependent RNA polymerase (L protein) by bridging nucleoprotein (N protein), which directly binds to viral genomic RNA, and L protein in the ribonucleoprotein complex (reviewed in reference 3). In addition, P protein functions to antagonize the type I interferon (IFN)-mediated antiviral responses by inhibiting both signaling pathways for IFN induction and response (4)(5)(6)(7)(8)(9)(10)(11)(12). P protein suppresses activation of interferon regulatory factor 3 (IRF-3), which is an important transcription factor for IFN induction (5,8).…”

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confidence: 99%

Roles of the Rabies Virus Phosphoprotein Isoforms in Pathogenesis

Okada

Ito

Yamaoka

et al. 2016

J Virol

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Rabies virus (RABV) P gene mRNA encodes five in-frame start codons, resulting in expression of full-length P protein (P1) and N-terminally truncated P proteins (tPs), designated P2, P3, P4, and P5. Despite the fact that some tPs are known as interferon (IFN) antagonists, the importance of tPs in the pathogenesis of RABV is still unclear. In this study, to examine whether tPs contribute to pathogenesis, we exploited a reverse genetics approach to generate CE(NiP)⌬P2-5, a mutant of pathogenic CE(NiP) in which the P gene was mutated by replacing all of the start codons (AUG) for tPs with AUA. We confirmed that while CE(NiP) expresses detectable levels of P2 and P3, CE(NiP)⌬P2-5 has an impaired ability to express these tPs. After intramuscular inoculation, CE(NiP)⌬P2-5 caused significantly lower morbidity and mortality rates in mice than did CE ( Rabies virus (RABV), a member of the genus Lyssavirus of the family Rhabdoviridae, is a zoonotic agent that causes a lethal neurological disease in various mammal species, including humans. After transmission via a bite wound caused by an infected animal, RABV infects peripheral nerves and then spreads to and in the central nervous system (CNS), resulting in severe neurological symptoms with a high case fatality rate of almost 100% (reviewed in reference 1). Due to the absence of an effective cure and insufficient provision of postexposure prophylaxis, approximately 59,000 people die from rabies every year, mainly in developing countries (2). To establish an effective cure and also to develop a novel prophylaxis approach for rabies, it is necessary to understand the molecular mechanisms of the pathogenesis, including immune evasion, of RABV.The phosphoprotein (P protein) of RABV is a multifunctional protein that is indispensable not only for viral replication but also for evasion of host innate immunity. Specifically, this protein plays an essential role in viral RNA synthesis as a cofactor of viral RNA-dependent RNA polymerase (L protein) by bridging nucleoprotein (N protein), which directly binds to viral genomic RNA, and L protein in the ribonucleoprotein complex (reviewed in reference 3). In addition, P protein functions to antagonize the type I interferon (IFN)-mediated antiviral responses by inhibiting both signaling pathways for IFN induction and response (4-12). P protein suppresses activation of interferon regulatory factor 3 (IRF-3), which is an important transcription factor for IFN induction (5, 8). Also, P protein binds to the transcriptional factors signal transducers and activator of transcription 1 (STAT1) and STAT2, which play a key role in the IFN response by activating expression of IFN-stimulated genes (ISGs), and inhibits their nuclear translocation and DNA binding (6,10,11).In RABV-infected cells, mRNA of the P gene is translated from five in-frame start codons by a ribosomal leaky scanning mechanism, resulting in expression of full-length P protein (P1; 297 amino acids) and also less abundant expression of N-terminally truncated P proteins (t...

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“…The RABV phosphoprotein (P-protein) has critical roles in genome transcription/replication and antagonism of interferon (IFN)-dependent antiviral responses (2)(3)(4)(5)(6)(7)(8)(9). In infected cells, the P gene produces full-length P-protein (P1) and several N-terminally truncated isoforms, predominantly P2 and P3, via a ribosomal leaky scanning mechanism (7,10).…”

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Identification of a Role for Nucleolin in Rabies Virus Infection

Oksayan

Nikolić

David

et al. 2015

J Virol

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c Rabies virus replicates in the cytoplasm of host cells, but rabies virus phosphoprotein (P-protein) undergoes active nucleocytoplasmic trafficking. Here we show that the largely nuclear P-protein isoform P3 can localize to nucleoli and forms specific interactions with nucleolin. Importantly, depletion of nucleolin expression inhibits viral protein expression and infectious virus production by infected cells. This provides the first evidence that lyssaviruses interact with nucleolin and that nucleolin is important to lyssavirus infection.

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Interaction of Rabies Virus P-Protein With STAT Proteins is Critical to Lethal Rabies Disease

Abstract: These data represent direct evidence that P-protein-STAT interaction is critical to rabies, and provide novel insights into the mechanism by which RABV coordinates distinct functions in interferon antagonism and replication.

Cited by 71 publications

References 43 publications

Contribution of the interaction between the rabies virus P protein and I-kappa B kinase ϵ to the inhibition of type I IFN induction signalling

Contribution of the interaction between the rabies virus P protein and I-kappa B kinase ϵ to the inhibition of type I IFN induction signalling

Roles of the Rabies Virus Phosphoprotein Isoforms in Pathogenesis

Identification of a Role for Nucleolin in Rabies Virus Infection

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