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Non-structural proteins of arthropod-borne bunyaviruses: roles and functions.

Eifan S, Schnettler E, Dietrich I, Kohl A, Blomström AL - Viruses (2013)

Bottom Line: Many bunyaviruses are arthropod-borne, so-called arboviruses.Depending on the genus, bunyaviruses encode, in addition to the RNA-dependent RNA polymerase and the different structural proteins, one or several non-structural proteins.In this review, we will summarize current knowledge and understanding of insect-borne bunyavirus non-structural protein function(s) in vertebrate, plant and arthropod.

View Article: PubMed Central - PubMed

Affiliation: Department of Botany and Microbiology, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. anne-lie.blomstrom@slu.se.

ABSTRACT
Viruses within the Bunyaviridae family are tri-segmented, negative-stranded RNA viruses. The family includes several emerging and re-emerging viruses of humans, animals and plants, such as Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, La Crosse virus, Schmallenberg virus and tomato spotted wilt virus. Many bunyaviruses are arthropod-borne, so-called arboviruses. Depending on the genus, bunyaviruses encode, in addition to the RNA-dependent RNA polymerase and the different structural proteins, one or several non-structural proteins. These non-structural proteins are not always essential for virus growth and replication but can play an important role in viral pathogenesis through their interaction with the host innate immune system. In this review, we will summarize current knowledge and understanding of insect-borne bunyavirus non-structural protein function(s) in vertebrate, plant and arthropod.

Show MeSH

Related in: MedlinePlus

The mechanisms by which NSs of orthobunyaviruses and phleboviruses interfere with the host innate immune system. The NSs proteins of the different bunyaviruses display a variety of different mechanisms to interfere with the host antiviral defense. This is done both by inducing proteasome degradation of proteins such as PKR and RIG-I as well as interfering with the assembly and activation of the transcription machinery inducing a host cell transcription block and inhibiting IFN-β transcription.
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viruses-05-02447-f003: The mechanisms by which NSs of orthobunyaviruses and phleboviruses interfere with the host innate immune system. The NSs proteins of the different bunyaviruses display a variety of different mechanisms to interfere with the host antiviral defense. This is done both by inducing proteasome degradation of proteins such as PKR and RIG-I as well as interfering with the assembly and activation of the transcription machinery inducing a host cell transcription block and inhibiting IFN-β transcription.

Mentions: Knowledge of the interferon pathways of vertebrates and their role in innate antiviral defenses is increasingly detailed. Virus antagonism of these host responses is recognized as a key element in virus/host interactions [32]. The induction of IFN production in virus infected cells is dependent on the activation of different factors, such as the IFN regulatory factor 3 (IRF-3) and nuclear factor κB (NF-κB) that upon activation translocate from the cytoplasm into the nucleus and there are involved in initiation of IFN induction (Figure 2) [32,33]. The crucial role of orthobunyavirus NSs proteins in counteracting host responses is now well established. Indeed, several studies have shown that the actions of BUNV, SBV and LACV NSs proteins inhibit the production of IFN in infected cells (Figure 3) and if the NSs ORF is deleted in these viruses they display an attenuated phenotype both in vivo and in vitro [21,23,27,34]. In the brain LACV and LACV∆NSs replicate mainly in neurons, however, these infected neurons are not the major contributors to IFN-β production [35,36]. During LACV infection uninfected astrocytes and microglia are the main producers of IFN-β, while in infections with LACV∆NSs astrocytes are the dominant IFN-β producer. LACV NSs strongly inhibits IFN-β production in astrocytes while it does not affect the amount of IFN-β produced in microglia [36]. Much of the pioneering work on understanding how orthobunyaviruses inhibit induction has been carried out with BUNV. As discussed in more detail in Section 2.1.2, IRF-3 is activated by BUNV and BUNV∆NSs viruses to a similar extent and is shown to enter the nucleus upon infection [37,38]. Moreover, Protein kinase R (PKR) is also activated by BUNV infection, leading to the phosphorylation and activation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2) and NSs is not able to inhibit this activation. Streitenfeld et al. (2003) demonstrated that BUNV appears not to be sensitive to the antiviral effects of PKR in cell culture but in vivo PKR appears to have a minor contribution to host resistance [34]. However, it should be noted that in a study overexpressing PKR in HEK 293 cells PKR did display a clear antiviral effect, reducing viral replication about 10-fold [39]. In BUNV infection inhibition of transcription must occur downstream of transcription factor activation. Chromatin immunoprecipitation analysis revealed that BUNV NSs does not interfere with the RNA polymerase II binding to the IFN-β promoter. Instead, NSs of BUNV prevents the phosphorylation of serine 2 in the heptapeptide repeats (YSPTSPS) in the C-terminal domain (CTD) of RNA polymerase II (Figure 3) [38]. This attacks a fundamental process as phosphorylation of serine 2 of CTD is needed for mRNA elongation and 3’-end processing [40]; thus by interfering with phosphorylation of this residue, BUNV can induce a generalized transcriptional block including that of IFN-β gene transcription. However, BUNV NSs does not target CTD phosphorylation in insect cells, which may contribute to the establishment of persistent infection in these cells [38]. This inhibition of phosphorylation and consequently of transcription is believed to be mediated by the interaction between the C-terminus of BUNV NSs and the protein Med8 [41]. Med8 is a component of the Mediator complex, which regulates RNA polymerase II through interacting directly with the CTD [42]. Although the interaction of the C-terminus of NSs with Med8 is required [41], van Knippenberg et al. (2010) showed that the N-terminus of the NSs protein is also involved in transcription inhibition [43]. LACV triggers IFN induction through the RIG-I pathway and subsequently activation of IRF-3, and similar to BUNV, LACV virus targets RNA polymerase II in order to inhibit IFN transcription. This inhibition is not mediated through interaction with Med8 or inhibition of phosphorylation of CTD but through elimination of the hyperphosphorylated (IIo) form of RNA polymerase II via a proteasomal degradation pathway (Figure 3). NSs uses the DNA damage response (DDR) pathway to trigger the degradation of CTD-Ser-2 phosphorylated RNA polymerase II, which leads to transcriptional arrest [44]. Thus, NSs proteins are important IFN antagonists. However, incoming viruses are not resistant to the antiviral effects of IFN as treatment of cells with IFN prior to virus infection significantly reduces virus yield [34]. BUNV interferon-induced gene MTAP44 and in particular Viperin appear to be involved in restricting BUNV replication [39].


Non-structural proteins of arthropod-borne bunyaviruses: roles and functions.

Eifan S, Schnettler E, Dietrich I, Kohl A, Blomström AL - Viruses (2013)

The mechanisms by which NSs of orthobunyaviruses and phleboviruses interfere with the host innate immune system. The NSs proteins of the different bunyaviruses display a variety of different mechanisms to interfere with the host antiviral defense. This is done both by inducing proteasome degradation of proteins such as PKR and RIG-I as well as interfering with the assembly and activation of the transcription machinery inducing a host cell transcription block and inhibiting IFN-β transcription.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814597&req=5

viruses-05-02447-f003: The mechanisms by which NSs of orthobunyaviruses and phleboviruses interfere with the host innate immune system. The NSs proteins of the different bunyaviruses display a variety of different mechanisms to interfere with the host antiviral defense. This is done both by inducing proteasome degradation of proteins such as PKR and RIG-I as well as interfering with the assembly and activation of the transcription machinery inducing a host cell transcription block and inhibiting IFN-β transcription.
Mentions: Knowledge of the interferon pathways of vertebrates and their role in innate antiviral defenses is increasingly detailed. Virus antagonism of these host responses is recognized as a key element in virus/host interactions [32]. The induction of IFN production in virus infected cells is dependent on the activation of different factors, such as the IFN regulatory factor 3 (IRF-3) and nuclear factor κB (NF-κB) that upon activation translocate from the cytoplasm into the nucleus and there are involved in initiation of IFN induction (Figure 2) [32,33]. The crucial role of orthobunyavirus NSs proteins in counteracting host responses is now well established. Indeed, several studies have shown that the actions of BUNV, SBV and LACV NSs proteins inhibit the production of IFN in infected cells (Figure 3) and if the NSs ORF is deleted in these viruses they display an attenuated phenotype both in vivo and in vitro [21,23,27,34]. In the brain LACV and LACV∆NSs replicate mainly in neurons, however, these infected neurons are not the major contributors to IFN-β production [35,36]. During LACV infection uninfected astrocytes and microglia are the main producers of IFN-β, while in infections with LACV∆NSs astrocytes are the dominant IFN-β producer. LACV NSs strongly inhibits IFN-β production in astrocytes while it does not affect the amount of IFN-β produced in microglia [36]. Much of the pioneering work on understanding how orthobunyaviruses inhibit induction has been carried out with BUNV. As discussed in more detail in Section 2.1.2, IRF-3 is activated by BUNV and BUNV∆NSs viruses to a similar extent and is shown to enter the nucleus upon infection [37,38]. Moreover, Protein kinase R (PKR) is also activated by BUNV infection, leading to the phosphorylation and activation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2) and NSs is not able to inhibit this activation. Streitenfeld et al. (2003) demonstrated that BUNV appears not to be sensitive to the antiviral effects of PKR in cell culture but in vivo PKR appears to have a minor contribution to host resistance [34]. However, it should be noted that in a study overexpressing PKR in HEK 293 cells PKR did display a clear antiviral effect, reducing viral replication about 10-fold [39]. In BUNV infection inhibition of transcription must occur downstream of transcription factor activation. Chromatin immunoprecipitation analysis revealed that BUNV NSs does not interfere with the RNA polymerase II binding to the IFN-β promoter. Instead, NSs of BUNV prevents the phosphorylation of serine 2 in the heptapeptide repeats (YSPTSPS) in the C-terminal domain (CTD) of RNA polymerase II (Figure 3) [38]. This attacks a fundamental process as phosphorylation of serine 2 of CTD is needed for mRNA elongation and 3’-end processing [40]; thus by interfering with phosphorylation of this residue, BUNV can induce a generalized transcriptional block including that of IFN-β gene transcription. However, BUNV NSs does not target CTD phosphorylation in insect cells, which may contribute to the establishment of persistent infection in these cells [38]. This inhibition of phosphorylation and consequently of transcription is believed to be mediated by the interaction between the C-terminus of BUNV NSs and the protein Med8 [41]. Med8 is a component of the Mediator complex, which regulates RNA polymerase II through interacting directly with the CTD [42]. Although the interaction of the C-terminus of NSs with Med8 is required [41], van Knippenberg et al. (2010) showed that the N-terminus of the NSs protein is also involved in transcription inhibition [43]. LACV triggers IFN induction through the RIG-I pathway and subsequently activation of IRF-3, and similar to BUNV, LACV virus targets RNA polymerase II in order to inhibit IFN transcription. This inhibition is not mediated through interaction with Med8 or inhibition of phosphorylation of CTD but through elimination of the hyperphosphorylated (IIo) form of RNA polymerase II via a proteasomal degradation pathway (Figure 3). NSs uses the DNA damage response (DDR) pathway to trigger the degradation of CTD-Ser-2 phosphorylated RNA polymerase II, which leads to transcriptional arrest [44]. Thus, NSs proteins are important IFN antagonists. However, incoming viruses are not resistant to the antiviral effects of IFN as treatment of cells with IFN prior to virus infection significantly reduces virus yield [34]. BUNV interferon-induced gene MTAP44 and in particular Viperin appear to be involved in restricting BUNV replication [39].

Bottom Line: Many bunyaviruses are arthropod-borne, so-called arboviruses.Depending on the genus, bunyaviruses encode, in addition to the RNA-dependent RNA polymerase and the different structural proteins, one or several non-structural proteins.In this review, we will summarize current knowledge and understanding of insect-borne bunyavirus non-structural protein function(s) in vertebrate, plant and arthropod.

View Article: PubMed Central - PubMed

Affiliation: Department of Botany and Microbiology, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. anne-lie.blomstrom@slu.se.

ABSTRACT
Viruses within the Bunyaviridae family are tri-segmented, negative-stranded RNA viruses. The family includes several emerging and re-emerging viruses of humans, animals and plants, such as Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, La Crosse virus, Schmallenberg virus and tomato spotted wilt virus. Many bunyaviruses are arthropod-borne, so-called arboviruses. Depending on the genus, bunyaviruses encode, in addition to the RNA-dependent RNA polymerase and the different structural proteins, one or several non-structural proteins. These non-structural proteins are not always essential for virus growth and replication but can play an important role in viral pathogenesis through their interaction with the host innate immune system. In this review, we will summarize current knowledge and understanding of insect-borne bunyavirus non-structural protein function(s) in vertebrate, plant and arthropod.

Show MeSH
Related in: MedlinePlus