Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids

Kochs, Georg; Haller, Otto

doi:10.1073/pnas.96.5.2082

Cited by 181 publications

(130 citation statements)

References 48 publications

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“…In measles virus-infected U-937 cells, viral protein synthesis is reduced by expression of MxA (16). Recently, George Kochs and Otto Haller have shown that MxA blocks nuclear import of nucleocapsids of Thogoto virus which replicates in nuclei (8). An earlier report (12) and this study indicate that MxA inhibits viral protein synthesis in influenza virus-infected cells.…”

Section: Discussionmentioning

confidence: 57%

Promoted Cell Death of Cells Expressing Human MxA by Influenza Virus Infection

Nakade

Nagata

2002

Microbiology and Immunology

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Interferon‐inducible MxA protein plays a crucial role in cellular protection from RNA virus infection, although the protection mechanism is not completely clarified. Here, we examined effects of MxA on either uninfected or influenza virus A/PR/8/34‐infected cells. Viral protein synthesis was reduced in cells expressing MxA. Under serum‐starved conditions, not only viral but also cellular protein synthesis was reduced by expression of MxA. Of interest is that MxA promoted cell death induced by apoptotic stimuli as well as influenza virus infection. These results lead to a possibility that MxA suppresses multiplication of influenza virus by affecting cellular functions including the apoptotic pathway.

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Section: Discussionmentioning

confidence: 57%

Promoted Cell Death of Cells Expressing Human MxA by Influenza Virus Infection

Nakade

Nagata

2002

Microbiology and Immunology

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“…Mx proteins are dynamin superfamily GTPases that act on a wide range of viruses by binding target viral proteins to inhibit virus replication. For example, MxA can bind to the nucleocapsid of Thogoto virus and block nuclear import [125].…”

Section: Resultsmentioning

confidence: 99%

The host type I interferon response to viral and bacterial infections

et al. 2005

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Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNs are produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN production were largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infections by recognizing various viral components. Furthermore, much progress has been made in defining the signaling pathways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally important in inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellular viral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also induce the up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type I IFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. This review will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.

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“…THOV is highly sensitive to the action of type I interferons (IFN), mostly mediated by the IFN-induced antiviral Mx proteins Kochs & Haller, 1999;Pavlovic et al, 1995). In order to avoid the antiviral effects of IFN, THOV developed a strategy to suppress the induction of the IFN system.…”

Section: Introductionmentioning

confidence: 99%

Thogoto virus ML protein is a potent inhibitor of the interferon regulatory factor-7 transcription factor

Buettner

Vogt

Martínez-Sobrido

et al. 2009

Journal of General Virology

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The tick-transmitted orthomyxovirus Thogoto virus (THOV) encodes the ML protein acting as a viral suppressor of the host interferon (IFN) system. Here, we describe that type I IFN is strongly induced in primary mouse embryo fibroblasts as well as plasmacytoid dendritic cells upon infection with a THOV mutant lacking the ML gene. However, wild-type THOV encoding ML suppresses induction of IFN by preventing the activation of members of the IFN regulatory factor (IRF) family. We found that reporter gene expression dependent on IRF3 and IRF7 was strongly inhibited by ML. Further experiments revealed that ML interacts with IRF7 and prevents dimerization of the transcription factor and its association with the coactivator TRAF6. Interestingly, another IRF7 activation step, nuclear translocation, is not affected by ML. Our data elucidate ML protein as a virulence factor with an IRF-specific IFN-antagonistic spectrum. INTRODUCTIONThogoto virus (THOV) is a tick-transmitted orthomyxovirus with a genome consisting of six single-stranded RNA segments that encode seven structural proteins (Hagmaier et al., 2004;Nuttall et al., 1995;van Regenmortel et al., 2000). THOV is highly sensitive to the action of type I interferons (IFN), mostly mediated by the IFN-induced antiviral Mx proteins Kochs & Haller, 1999;Pavlovic et al., 1995). In order to avoid the antiviral effects of IFN, THOV developed a strategy to suppress the induction of the IFN system. We have previously shown that the ML protein, an extended version of the viral matrix (M) protein, is a viral IFN antagonist (Hagmaier et al., 2003(Hagmaier et al., , 2004. Previous work with a recombinant THOV lacking ML expression showed that ML is essential for virus growth and pathogenesis in an IFN-competent host (Pichlmair et al., 2004). Further studies demonstrated that in the presence of ML the activation and/or action of the interferon regulatory factor-3 (IRF3) is severely affected (Jennings et al., 2005). This effect depends on direct interaction of ML with the transcription factor IIB (TFIIB) (Vogt et al., 2008), suggesting that complex formation of ML with TFIIB specifically disturbs the function of certain transcription coactivators such as IRF3.Members of the IRF family of transcription factors are involved in all aspects of IFN induction and action (Haller et al., 2006;Mamane et al., 1999;Randall & Goodbourn, 2008;Taniguchi & Takaoka, 2002). IRF3 is constitutively expressed in most cells and is essential for the induction of IFN-b as an early response to virus infection (Lin et al., 1998; Yoneyama et al., 1998) or to Toll-like receptor (TLR) agonists like dsRNA or lipopolysaccharide that bind to TLR3 and TLR4, respectively (Pitha, 2004). A positive feedback loop then leads to the induction of IRF7, which upon activation by virus infection leads to the amplification of the IFN signal mainly by transcriptional activation of the IFN-a genes in addition to IFN-b (Marie et al., 1998;Sato et al., 1998).Two independent signal transduction pathways lead to the activation of ...

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Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids

Cited by 181 publications

References 48 publications

Promoted Cell Death of Cells Expressing Human MxA by Influenza Virus Infection

Promoted Cell Death of Cells Expressing Human MxA by Influenza Virus Infection

The host type I interferon response to viral and bacterial infections

Thogoto virus ML protein is a potent inhibitor of the interferon regulatory factor-7 transcription factor

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