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TRIM25 Is Required for the Antiviral Activity of Zinc-finger Antiviral Protein (ZAP).

TRIM25 Is Required for the Antiviral Activity of Zinc-finger Antiviral Protein (ZAP).
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Zheng X, Wang X, Tu F, Wang Q, Fan Z, Gao G,


Zheng X, Wang X, Tu F, Wang Q, Fan Z, Gao G, (click to view)

Zheng X, Wang X, Tu F, Wang Q, Fan Z, Gao G,

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Journal of virology 2017 02 15() pii 10.1128/JVI.00088-17

Abstract

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 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 represses the translation and promotes the degradation of target mRNA. While the mechanisms by which ZAP post-transcriptionally inhibits target RNA expression has 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 to better understand how the antiviral activity of ZAP is regulated.

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