Interaction of Bunyamwera Orthobunyavirus NSs Protein with Mediator Protein MED8: a Mechanism for Inhibiting the Interferon Response

Léonard, Vincent H. J.; Kohl, Alain; Hart, Timothy J.; Elliott, Richard M.

doi:10.1128/jvi.00822-06

Cited by 73 publications

(94 citation statements)

References 52 publications

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“…Control RT-PCRs for the LACV N gene showed that viruses replicated to comparable levels, and RT-PCRs for the cellular ␤-actin mRNA demonstrated that all preparations contained similar amounts of RNA. Of note, RT-PCR analysis for some RNA polymerase II-dependent, constitutively expressed cellular genes shows a strong reduction in wt-infected cells (6), supporting the view that LACV NSs may influence cellular transcription in a manner similar to BUNV NSs and RVFV (32,33,51).…”

Section: Inhibition Of Ifn Induction In Fibroblastsmentioning

confidence: 68%

La Crosse Bunyavirus Nonstructural Protein NSs Serves To Suppress the Type I Interferon System of Mammalian Hosts

Blakqori

Delhaye

Habjan

et al. 2007

J Virol

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160

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Section: Inhibition Of Ifn Induction In Fibroblastsmentioning

confidence: 68%

La Crosse Bunyavirus Nonstructural Protein NSs Serves To Suppress the Type I Interferon System of Mammalian Hosts

Blakqori

Delhaye

Habjan

et al. 2007

J Virol

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160

180

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“…Previous results have shown that TOSV activates transcription of IFN-␤ during infection, in contrast to that observed for other members of the Bunyaviridae family (9). In fact, many of these viruses possess the nonstructural protein NSs, which counteracts IFN-␤ production, resulting in viral escape from the host immune response (15,17,20,(24)(25)(26)(27)(28)(29). To better address the mechanisms which regulate IFN-␤ production in TOSV infection, the role of RIG-I was investigated.…”

Section: Resultsmentioning

confidence: 99%

Toscana Virus NSs Protein Inhibits the Induction of Type I Interferon by Interacting with RIG-I

Savellini

Valentini

Cusi

2013

J Virol

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Toscana virus (TOSV) is a phlebovirus, of the. In this study, we investigated whether an upstream sensor, which has a role in the signaling cascade leading to the production of type I IFN, was involved. We found a significant decrease in RIG-I protein levels in cells overexpressing TOSV NSs, suggesting that the nonstructural protein interacts with RIG-I and targets it for proteasomal degradation. In fact, the MG-132 proteasome inhibitor was able to restore IFN-␤ promoter activation in cells expressing NSs, demonstrating the existence of an evasion mechanism based on inhibition of the RIG-I sensor. Furthermore, a C-terminal truncated NSs protein (⌬NSs), although able to interact with RIG-I, did not affect the RIG-I-mediated IFN-␤ promoter activation, suggesting that the NSs domains responsible for RIG-I-mediated signaling and interaction with RIG-I are mapped on different regions. These results contribute to identify a novel mechanism for bunyaviruses by which TOSV NSs counteracts the early IFN response.

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“…LACV NSs does not interact with MED 8 or p44 (data not shown), the host cell factors mediating RNAP II inhibition by the NSs proteins of BUNV and RVFV, respectively (23,58). Moreover, unlike what was shown for herpes simplex virus (75), a dominant-negative form of HSC70 cannot rescue RNAP IIo degradation by LACV infection (data not shown).…”

Section: Discussionmentioning

confidence: 84%

“…Both these viruses encode NSs proteins, which, although being different in sequence, size, and mode of expression, act on the level of general host cell transcription. BUNV (which is closely related to LACV) expresses an NSs, which interferes with the phosphorylation on CTD-Ser-2 (25) and interacts with MED8, a component of the Mediator transcription complex (58). The Mediator complex is involved in RNAP II regulation (59) and contacts the CTD-Ser-2 kinase P-TEFb (60).…”

Section: Discussionmentioning

confidence: 99%

Interferon Antagonist NSs of La Crosse Virus Triggers a DNA Damage Response-like Degradation of Transcribing RNA Polymerase II

Verbruggen

Ruf

Blakqori

et al. 2011

Journal of Biological Chemistry

107

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La Crosse encephalitis virus (LACV) is a mosquito-borne member of the negative-strand RNA virus family Bunyaviridae. We have previously shown that the virulence factor NSs of LACV is an efficient inhibitor of the antiviral type I interferon system. A recombinant virus unable to express NSs (rLACVdelNSs) strongly induced interferon transcription, whereas the corresponding wt virus (rLACV) suppressed it. Here, we show that interferon induction by rLACVdelNSs mainly occurs through the signaling pathway leading from the pattern recognition receptor RIG-I to the transcription factor IRF-3. NSs expressed by rLACV, however, acts downstream of IRF-3 by specifically blocking RNA polymerase II-dependent transcription. Further investigations revealed that NSs induces proteasomal degradation of the mammalian RNA polymerase II subunit RPB1. NSs thereby selectively targets RPB1 molecules of elongating RNA polymerase II complexes, the so-called IIo form. This phenotype has similarities to the cellular DNA damage response, and NSs was indeed found to transactivate the DNA damage response gene pak6. Moreover, NSs expressed by rLACV boosted serine 139 phosphorylation of histone H2A.X, one of the earliest cellular reactions to damaged DNA. However, other DNA damage response markers such as up-regulation and serine 15 phosphorylation of p53 or serine 1524 phosphorylation of BRCA1 were not triggered by LACV infection. Collectively, our data indicate that the strong suppression of interferon induction by LACV NSs is based on a shutdown of RNA polymerase II transcription and that NSs achieves this by exploiting parts of the cellular DNA damage response pathway to degrade IIo-borne RPB1 subunits. La Crosse virus (LACV)3 is a mosquito-borne member of the family Bunyaviridae, genus Orthobunyavirus. LACV infections are an important cause of severe encephalitis and meningitis in children and young adults in the Western United States (1-3). Around 75-100 cases per year require hospitalizations (4), and more than 10% of those patients will have long-lasting neurological deficits (1, 5). Recent observations suggest that the virus is spreading to new geographic regions (6).Like other arboviruses, LACV cycles between vertebrate and invertebrate hosts, being able to replicate both in mammals and in insects. Depending on the host, however, the outcome of infection is different (7). In mammalian cells, infection is lytic and causes host cell shutoff and cell death. In insect cells infection is non-cytolytic and leads to long term viral persistence.LACV is enveloped and has a tri-segmented singlestranded RNA genome of negative-sense polarity. Transcription and replication of the genome occur in the cytoplasm, and particles bud into the Golgi apparatus before being secreted. The viral genome encodes four structural proteins, the viral polymerase (L) on the large (L) segment, two glycoproteins (Gn and Gc) on the medium (M) segment, and the viral nucleocapsid protein (N) on the smallest (S) segment. In addition, LACV expresses two nonstructural protei...

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Interaction of Bunyamwera Orthobunyavirus NSs Protein with Mediator Protein MED8: a Mechanism for Inhibiting the Interferon Response

Cited by 73 publications

References 52 publications

La Crosse Bunyavirus Nonstructural Protein NSs Serves To Suppress the Type I Interferon System of Mammalian Hosts

La Crosse Bunyavirus Nonstructural Protein NSs Serves To Suppress the Type I Interferon System of Mammalian Hosts

Toscana Virus NSs Protein Inhibits the Induction of Type I Interferon by Interacting with RIG-I

Interferon Antagonist NSs of La Crosse Virus Triggers a DNA Damage Response-like Degradation of Transcribing RNA Polymerase II

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