TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein
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Published on: December 21, 2019
Xiaojiao Zheng1,2, Xinlu Wang1, Fan Tu1
1CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
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 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.
Insights
The antiviral protein Zinc finger antiviral protein (ZAP) requires tripartite motif-containing protein 25 (TRIM25) for its function. TRIM25, a ubiquitin E3 ligase, is essential for ZAP
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Zinc finger antiviral protein (ZAP) is a host factor that inhibits viral replication by targeting viral mRNA.
- The precise mechanisms regulating ZAP's antiviral activity remain incompletely understood.
- Understanding ZAP regulation is crucial for developing antiviral strategies against viruses like HIV-1 and Ebola virus.
Purpose of the Study:
- To investigate the role of tripartite motif-containing protein 25 (TRIM25) in regulating ZAP's antiviral activity.
- To elucidate the molecular mechanisms by which TRIM25 influences ZAP function.
- To identify host factors essential for ZAP-mediated antiviral responses.
Main Methods:
- Knockdown of endogenous TRIM25 to assess its effect on ZAP activity.
- Assessing the requirement of TRIM25's E3 ligase activity for ZAP regulation.
- Investigating ZAP ubiquitination mediated by TRIM25.
- Evaluating the impact of ubiquitin or deubiquitinase manipulation on ZAP activity.
- Analyzing TRIM25's effect on ZAP's target RNA binding.
Main Results:
- Downregulation of TRIM25 abolished ZAP's antiviral activity, highlighting TRIM25's essential role.
- TRIM25's E3 ligase activity is necessary for regulating ZAP's antiviral function.
- TRIM25 mediates ZAP ubiquitination, although ZAP ubiquitination itself is not critical for its antiviral activity.
- Impaired ZAP activity was observed upon downregulation of ubiquitin or overexpression of OTUB1.
- TRIM25 was found to modulate ZAP's ability to bind target RNA.
Conclusions:
- TRIM25 is a critical host factor required for the antiviral activity of ZAP.
- TRIM25 regulates ZAP function, at least in part, by modulating its target RNA binding.
- These findings reveal a novel regulatory mechanism for ZAP's antiviral activity, enhancing our understanding of host-pathogen interactions.
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