One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

Gonzalez-Perez, Ana Cristina; Stempel, Markus; Chan, Baca; Brinkmann, Melanie M.

doi:10.3389/fmicb.2020.00124

Cited by 15 publications

(17 citation statements)

References 83 publications

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“…Herpesviruses have developed numerous strategies to evade or impede the host immune response including PRR-signaling and downstream effectors [13,14]. Recently, we identified the murine CMV (MCMV) M35 protein as a type I IFN antagonist that downmodulates type I IFN transcription downstream of multiple PRR [15].…”

Section: Introductionmentioning

confidence: 99%

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

et al. 2020

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The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.

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Section: Introductionmentioning

confidence: 99%

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

et al. 2020

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“…However, we did not observe an effect for ZAP-S on IFN signalling pathways, which likely corresponds with HCMV encoding multiple viral evasion proteins that downmodulate the IFN response (Gonzalez-Perez et al, 2020;Stempel et al, 2019). Hence, a possible effect of ZAP-S in this regard may be overshadowed in the context of infection with this complex herpesvirus.…”

Section: Discussionmentioning

confidence: 56%

“…ISG function is highly contextual as their effect on viral infection is dependent on the viral entry route, replication mechanism, site of replication and viral assembly, and cell type. Hence, while some ISGs may exert an antiviral activity against some viruses, they may either have a neutral or positive effect on other viruses, or in some instances, be susceptible to viral evasion mechanisms (Gonzalez-Perez et al, 2020;Schoggins et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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The zinc finger antiviral protein ZAP destabilises viral transcripts and restricts human cytomegalovirus

Gonzalez-Perez

Stempel

Wyler

et al. 2020

Preprint

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Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonises several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is largely unknown. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a β-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. We show that expression of the two major isoforms of ZAP, the long (ZAP-L) and short (ZAP-S), is induced during HCMV infection and that both negatively affect HCMV replication. Transcriptome and proteome analyses demonstrated that the expression of ZAP decelerates the progression of HCMV infection. SLAM-sequencing revealed that ZAP restricts HCMV at early stages of infection by destabilising a distinct subset of viral transcripts with low CG content. In summary, this report provides evidence of an important antiviral role for ZAP in host defense against HCMV infection and highlights its differentiated function during DNA virus infection.

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“…Through signaling on certain cell surfaces, IFN finally mediates diverse ISG expressions, some of which have been found to exert antiviral effects. Recently, some herpesviral antagonists were demonstrated to target ISGs (Gonzalez-Perez et al, 2020). CXCL10, one of the proinflammatory cytokines, participates in various processes such as apoptosis, chemotaxis, and differentiation (Liu et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus UL23 Attenuates Signal Transducer and Activator of Transcription 1 Phosphorylation and Type I Interferon Response

Feng

et al. 2021

Front. Microbiol.

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Human cytomegalovirus (HCMV), the human beta-herpesvirus, can cause severe syndromes among both immunocompromised adult patients and newborns. Type I interferon (IFN-I) exerts an important effect to resist infections caused by viruses such as HCMV, while IFN evasion may serve as a key determining factor for viral dissemination and disease occurrence within hosts. In this study, UL23, a tegument protein of HCMV, was confirmed to be a key factor for negatively regulating the type I IFN immune response. A detailed analysis indicated that the viral UL23 protein increases the IFN-I antiviral resistance during HCMV infections. Furthermore, UL23 was shown to significantly reduce the levels of IFN-stimulated genes (ISGs) and promoter activity of IFN-I-stimulated response element. Mechanically, UL23 was discovered to impair the signal transducer and activator of transcription 1 (STAT1) phosphorylation, although it was not found to affect phosphorylation and expression of STAT2, Janus activated kinase 1, or tyrosine kinase 2, which are associated with IFN-I signal transduction pathway. Additionally, a significantly reduced nuclear expression of STAT1 but not of IFN regulatory factor 9 or STAT2 was observed. Findings of this study indicate that HCMV UL23 is a viral antagonist that acts against the cellular innate immunity and reveal a possible novel effect of UL23 on IFN-I signaling.

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One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

Cited by 15 publications

References 83 publications

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

The zinc finger antiviral protein ZAP destabilises viral transcripts and restricts human cytomegalovirus

Human Cytomegalovirus UL23 Attenuates Signal Transducer and Activator of Transcription 1 Phosphorylation and Type I Interferon Response

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