Inhibition of Filovirus Replication by the Zinc Finger Antiviral Protein

Müller, Stefanie; Möller, Peggy; Bick, Matthew J.; Wurr, Stephanie; Becker, Stephan; Günther, Stephan; Kümmerer, Beate M.

doi:10.1128/jvi.01601-06

Cited by 188 publications

(179 citation statements)

References 24 publications

(36 reference statements)

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“…Since filoviruses encode their own replication/transcription machinery, the components involved in replication/transcription; cis-acting elements on the genomes and VPs mediating replication/transcription, are ideal targets for antiviral strategies. Indeed, initial approaches to use viral genes and proteins involved in replication/transcription as targets for antiviral compounds were quite promising [59,63,[67][68][69][70]. Thus, a deeper understanding of the way in which filoviruses replicate and transcribe their genomes will lead to potential benefits in controlling filovirus infections.…”

Section: Future Perspectivementioning

confidence: 99%

Filovirus Replication and Transcription

2007

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The highly pathogenic filoviruses, Marburg and Ebola virus, belong to the nonsegmented negative-sense RNA viruses of the order Mononegavirales. The mode of replication and transcription is similar for these viruses. On one hand, the negative-sense RNA genome serves as a template for replication, to generate progeny genomes, and, on the other hand, for transcription, to produce mRNAs. Despite the similarities in the replication/transcription strategy, filoviruses have evolved structural and functional properties that are unique among the nonsegmented negativesense RNA viruses. Moreover, there are also striking differences in the replication and transcription mechanisms of Marburg and Ebola virus. This includes nucleocapsid formation, the structure of the genomic replication promoter, the protein requirement for transcription and the use of mRNA editing. In this article, the current knowledge of the replication and transcription strategy of Marburg and Ebola virus is reviewed, with focus on the observed differences.

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Section: Future Perspectivementioning

confidence: 99%

Filovirus Replication and Transcription

2007

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“…In addition to MLV, overexpression of ZAP also inhibits the replication of Ebola virus and Marburg virus (2), and several members of the Alphavirus genus, including Sindbis virus (SINV) (3). IFN treatment or SINV infection of murine bone marrow-derived dendritic cells significantly up-regulates the expression level of ZAP (4), suggesting that ZAP also may function as an antiviral effector in vivo.…”

mentioning

confidence: 99%

p72 DEAD box RNA helicase is required for optimal function of the zinc-finger antiviral protein

Chen

Guo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

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The zinc-finger antiviral protein (ZAP) specifically inhibits the replication of many viruses by preventing the accumulation of viral mRNAs in the cytoplasm. ZAP directly binds to the viral mRNAs and recruits the RNA exosome to degrade the target RNA. In the present study, we identified the p72 DEAD box RNA helicase, but not the highly similar RNA helicase p68, as a ZAP-interacting protein. The binding domain of ZAP was mapped to its N-terminal portion, whereas both the N-and C-terminal domains of p72 bound to ZAP. Overexpression of the C-terminal domain of p72 reduced ZAP's activity, whereas overexpression of the full-length p72 enhanced ZAP's activity. The RNA helicase activity was required for p72 to promote ZAP-mediated RNA degradation. Depletion of p72 by RNAi also reduced ZAP's activity but did not affect tristetraprolin-mediated RNA degradation. We conclude that p72 is required for the optimal activity of ZAP, and we propose that p72 helps to restructure the ZAP-bound target mRNA for efficient degradation.restriction ͉ RNA degredation ͉ retrovirus ͉ alphavirus T he zinc-finger antiviral protein (ZAP) was initially recovered as a host factor that inhibited the infection of cells by Moloney murine leukemia virus (MLV) (1). In addition to MLV, overexpression of ZAP also inhibits the replication of Ebola virus and Marburg virus (2), and several members of the Alphavirus genus, including Sindbis virus (SINV) (3). IFN treatment or SINV infection of murine bone marrow-derived dendritic cells significantly up-regulates the expression level of ZAP (4), suggesting that ZAP also may function as an antiviral effector in vivo. However, ZAP is not a universal antiviral factor; some viruses, including herpes simplex virus type 1 and yellow fever virus, grow normally in ZAP-expressing cells (3).ZAP inhibits virus replication by preventing the accumulation of the viral mRNA in the cytoplasm (1-3). In the N terminus of ZAP, there are four CCCH-type zinc-finger motifs (1). ZAP directly binds to specific viral mRNA sequences [ZAPresponsive element (ZRE)] through the CCCH-type zinc fingers (5). Furthermore, ZAP directly interacts with the RNAprocessing exosome (6), a 3Ј-5Ј exoribonucleases complex consisting of at least nine components (7). The current working model is that ZAP promotes the degradation of ZRE-containing mRNAs by directly binding to the target RNA and recruiting the exosome to degrade the RNA (6).The p72 RNA helicase is a member of the DEAD box family of RNA helicases, which are characterized by a conserved motif including Asp-Glu-Ala-Asp (DEAD) and involved in various biological processes (8,9). Compared with other DEAD box RNA helicases, p72 has a unique N-terminal domain containing repeats of the sequence RGG and a C-terminal domain rich in serine and glycine and terminating with a polyproline region (10). p72 is highly related to the better known p68 RNA helicase; they share Ϸ90% sequence identity in the core region spanning the conserved motifs characteristic of this family and 69.7% overall homology (10)...

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“…In addition to MMLV, ZAP inhibits the replication of HIV-1 (2), Ebola virus and Marburg virus (3), and certain alphaviruses such as Sindbis virus, Ross River virus, and Semliki Forest virus (4,5). ZAP is not a universal antiviral factor because it does not inhibit the replication of viruses such as poliovirus and yellow fever virus (5).…”

mentioning

confidence: 99%

“…The zinc-finger antiviral protein (ZAP) 3 was originally isolated as a host factor that inhibits the replication of Moloney murine leukemia virus (MMLV) (1). In addition to MMLV, ZAP inhibits the replication of HIV-1 (2), Ebola virus and Marburg virus (3), and certain alphaviruses such as Sindbis virus, Ross River virus, and Semliki Forest virus (4,5).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase 3β (GSK3β) Modulates Antiviral Activity of Zinc-finger Antiviral Protein (ZAP)

Sun¹,

Lv²,

Guo

et al. 2012

Journal of Biological Chemistry

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Background: Zinc-finger antiviral protein (ZAP) is a type I interferon-inducible host antiviral factor against certain viruses, including HIV-1 and Ebola virus. Results: Glycogen synthase kinase 3␤ (GSK3␤) phosphorylates ZAP, and inhibition of GSK3␤ reduces ZAP activity. Conclusion: GSK3␤ phosphorylation of ZAP modulates its antiviral activity. Significance: These findings help to better understand how the immune response is regulated.

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Inhibition of Filovirus Replication by the Zinc Finger Antiviral Protein

Cited by 188 publications

References 24 publications

Filovirus Replication and Transcription

Filovirus Replication and Transcription

p72 DEAD box RNA helicase is required for optimal function of the zinc-finger antiviral protein

Glycogen Synthase Kinase 3β (GSK3β) Modulates Antiviral Activity of Zinc-finger Antiviral Protein (ZAP)

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