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

Sun, Lin; Lv, Fengxiang; Guo, Xiaohong; Gao, Guangxia

doi:10.1074/jbc.m111.306373

Cited by 17 publications

(23 citation statements)

References 33 publications

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“…It is possible that prenylation positions ZAPL in membrane compartments, allowing it to target viruses with an endocytic life cycle step. In addition, phosphorylation of ZAP by glycogen synthase kinase 3β positively modulates ZAP activity potentially by enhancing its ability to inhibit mRNA translation [34]. Moreover, when cells are stressed, ZAP localizes to cytoplasmic stress granules and is modified by poly-ADP-ribosylation [35].…”

Section: Discussionmentioning

confidence: 99%

TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP)

et al. 2017

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The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP’s antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP’s ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity.

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Section: Discussionmentioning

confidence: 99%

TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP)

et al. 2017

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“…Posttranslational modification of ZAP has been reported to modulate ZAP's activity. Phosphorylation by glycogen synthase kinase 3␤ (GSK3␤) enhances the antiviral activity of ZAP (17). S-Farnesylation of ZAPL but not ZAPS enhances the antiviral activity (18).…”

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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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130

168

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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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“…Secondary RNA structures present in both RRs could be potential targets for the antiviral protein ZAP (Chen et al, 2012; Gao et al, 2002; Guo et al, 2007). ZAP, an IRF3-induced, (GSK3-beta)-modulated protein is upregulated in the presence of viral double-stranded RNA and shows specific activity toward filovirus RNAs (Muller et al, 2007; Sun et al, 2012; Wang et al, 2010). Transient expression of rZAP (the rat analog of ZAP) and MARV bicistronic minigenomes identified the VP30 mRNA 5′UTR as a major ZAP target, while other UTRs went mostly unrecognized by its antiviral activity.…”

Section: Discussionmentioning

confidence: 99%

Sequence variability in viral genome non-coding regions likely contribute to observed differences in viral replication amongst MARV strains

Alonso

2013

Virology

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The Marburg viruses Musoke (MARV-Mus) and Angola (MARV-Ang) have highly similar genomic sequences. Analysis of viral replication using various assays consistently identified MARV-Ang as the faster replicating virus. Non-coding genomic regions of negative sense RNA viruses are known to play a role in viral gene expression. A comparison of the six non-coding regions using bicistronic minigenomes revealed that the first two non-coding regions (NP / VP35 and VP35 / VP40) differed significantly in their transcriptional regulation. Deletion mutation analysis of the MARV-Mus NP / VP35 region further revealed that the MARV polymerase (L) is able to initiate production of the downstream gene without the presence of highly conserved regulatory signals. Bicistronic minigenome assays also identified the VP30 mRNA 5′ untranslated region as an rZAP-targeted RNA motif. Overall, our studies indicate that the high variation of MARV non-coding regions may play a significant role in observed differences in transcription and/or replication.

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

Cited by 17 publications

References 33 publications

TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP)

TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP)

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

Sequence variability in viral genome non-coding regions likely contribute to observed differences in viral replication amongst MARV strains

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