Inhibition of Retroviral RNA Production by ZAP, a CCCH-Type Zinc Finger Protein

Gao, Guangxia; Guo, Xiaohong; Goff, Stephen P.

doi:10.1126/science.1074276

Cited by 407 publications

(513 citation statements)

References 17 publications

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“…Z inc finger antiviral protein (ZAP) is a type I interferon-inducible host factor that specifically inhibits the replication of certain viruses, including HIV-1, Sindbis virus (SINV), Ebola virus, hepatitis B virus, and murine leukemia virus (1)(2)(3)(4)(5)(6), as well as the retrotransposition of some retrotransposons (7,8). ZAP binds directly to the ZAPresponsive element (ZRE) in the viral mRNA, and it represses the translation and promotes the degradation of target mRNA (6,(9)(10)(11).…”

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confidence: 99%

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

Zheng

Wang

et al. 2017

J Virol

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Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mRNAs and repressing the translation and/or promoting the degradation of target mRNA. In addition, ZAP regulates the expression of certain cellular genes. Here, we report that tripartite motif-containing protein 25 (TRIM25), a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 abolished ZAP's antiviral activity. The E3 ligase activity of TRIM25 is required for this regulation. TRIM25 mediated ZAP ubiquitination, but the ubiquitination of ZAP itself did not seem to be required for its antiviral activity. Downregulation of endogenous ubiquitin or overexpression of the deubiquitinase OTUB1 impaired ZAP's activity. We provide evidence indicating that TRIM25 modulates the target RNA binding activity of ZAP. These results uncover a mechanism by which the antiviral activity of ZAP is regulated.IMPORTANCE ZAP is a host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1, Sindbis virus, and Ebola virus. ZAP binds directly to target mRNA, and it represses the translation and promotes the degradation of target mRNA. While the mechanisms by which ZAP posttranscriptionally inhibits target RNA expression have been extensively studied, how its antiviral activity is regulated is not very clear. Here, we report that TRIM25, a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 remarkably abolished ZAP's activity. TRIM25 is required for ZAP optimal binding to target mRNA. These results help us to better understand how the antiviral activity of ZAP is regulated.

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confidence: 99%

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

Zheng

Wang

et al. 2017

J Virol

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113

150

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“…MLV-luc is a retroviral vector carrying a firefly luciferase reporter (Gao et al, 2002;Guo et al, 2004). To produce VSV_G pseudotyped MLV-luc vector, pMLV-luc was cotransfected into HEK293T cells with pVSVG, a plasmid expressing VSV_G, and pHIT60, a plasmid expressing MLV proteins.…”

Section: Overexpression Of Yb-1 Increased Retroviral Vector Productionmentioning

confidence: 99%

“…MLV-luc producing plasmids pCMV-VSVG, pHIT60 and pMA-Luc have been previously described (Gao et al, 2002;Guo et al, 2004).…”

Section: Plasmidsmentioning

confidence: 99%

Expression of YB-1 enhances production of murine leukemia virus vectors by stabilizing genomic viral RNA

Wang

Gao

2012

Protein Cell

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Murine leukemia virus (MLV)-based retroviral vectors iswidely used for gene transfer and basic research, and production of high-titer retroviral vectors is very important. Here we report that expression of the Y-box binding protein 1 (YB-1) enhanced the production of infectious MLV vectors. YB-1 specifically increased the stability of viral genomic RNA in virus-producing cells, and thus increasing viral RNA levels in both producer cells and virion particles. The viral element responsive to YB-1 was mapped to the repeat sequence (R region) in MLV genomic RNA. These results identified YB-1 as a MLV mRNA stabilizer, which can be used for improving production of MLV vectors.

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“…17,55,56 Furthermore, this protein also proved to exert a potent inhibitory effect on alphaviruses. Considering the exclusive cytoplasmic life cycle of the SFV, the nuclear-cytoplasm shuttling of ZAP might explain this observation.…”

Section: Cellular Factors and Sfv Vectorsmentioning

confidence: 99%