BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon
            <i>De Novo</i>
            Infection

Konishi, Natsuno; Narita, Yohei; Hijioka, Fumiya; Masud, H. M. Abdullah Al; Sato, Yoshitaka; Kimura, Hiroshi; Murata, Takayuki

doi:10.1128/msphere.00138-18

Cited by 30 publications

(47 citation statements)

References 46 publications

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“…Moreover, BGLF2 bound to the RHD of p65 and inhibited its nuclear translocation. Surprisingly, BGLF2 could not inhibit NF-kB-dependent cytokine IL-8 expression, which may be related to the BGLF2-induced activation of AP-1 and its subsequent expression of inflammatory factors (34,35). Furthermore, some EBV-encoded proteins, such as Epstein-Barr nuclear antigen 1, can enhance the activity of AP-1 transcription and inhibit the canonical NF-kB signaling pathway (26,27) to coexist with the host by enhancing or inhibiting different pathways (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…BGLF2 is a tegument protein that expressed with late kinetics in EBV-infected cells (33,64,65). Recently, BGLF2 has been shown to activate p38 and JNK signaling pathways and enhance AP-1-dependent transcription (34,35). Several orthologs of BGLF2, such as Kaposi's sarcomaassociated herpesvirus ORF33 (66,67), varicella-zoster virus ORF44 (68), and cytomegalovirus (CMV) unique long 94 (UL94) (69), are essential for viral replication.…”

Section: Discussionmentioning

confidence: 99%

“…As a potential tegument protein, BGLF2 is important for the re-envelopment of EBV in the cytoplasm or plasma membrane, which can be detected in the mature virions (33). It has been reported that BGLF2 can increase EBV infectivity by activating the AP-1 signaling pathway through phosphorylation of p38 and JNK (34,35). However, whether BGLF2 is involved in regulating NF-kB signaling is still unknown.…”

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confidence: 99%

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Epstein‐Barr virus tegument protein BGLF2 inhibits NF‐κB activity by preventing p65 Ser536 phosphorylation

et al. 2019

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Epstein‐Barr virus (EBV), a ubiquitous gammaherpesvirus, can regulate the antiviral response of NF‐κB signaling, which is critical for cell survival, growth transformation, and virus latency. Here, we showed that tegument protein BGLF2 could inhibit TNF‐α‐induced NF‐κB activity. BGLF2 was shown to interplay with the NF‐κB subunits p65 and p50, and the Rel homology domain of p65 was the pivotal region to interact with BGLF2. Nonetheless, BGLF2 did not influence the development of p65‐p50 dimerization. Yet, overexpression of BGLF2 inhibited the phosphorylation of p65 Ser536 (but not Ser276) and blocked the nuclear translocation of p65. In addition, knockdown of BGLF2 during EBV lytic replication elevated NF‐κB activity and the phosphorylation of p65 Ser536. Taken together, these results suggest that the inhibition of NF‐κB activation may serve as a strategy to escape the host's antiviral innate immunity to EBV during its lytic infection.—Chen, T., Wang, Y., Xu, Z., Zou, X., Wang, P., Ou, X., Li, Y., Peng, T., Chen, D., Li, M., Cai, M. Epstein‐Barr virus tegument protein BGLF2 inhibits NF‐κB activity by preventing p65 Ser536 phosphorylation. FASEB J. 33, 10563–10576 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Epstein‐Barr virus tegument protein BGLF2 inhibits NF‐κB activity by preventing p65 Ser536 phosphorylation

et al. 2019

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“…In addition to HCMV, other herpesviruses modulate AP-1 during infection. The Epstein Barr virus (EBV) protein, BGLF2, and the Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded ORF45 both activate the AP-1 signaling pathway to promote viral gene expression, replication, and survival (37, 38). EBV also encodes an AP-1 homolog, BZLF1, which, like AP-1, supports resting B cell proliferation and binds methylated EBV promoters critical for reactivation (39).…”

Section: Discussionmentioning

confidence: 99%

Activator protein-1 transactivation of the major immediate early locus is a determinant of cytomegalovirus reactivation from latency

Krishna

Wass

O’Connor

2020

Preprint

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Human cytomegalovirus (HCMV) is a ubiquitous pathogen that latently infects hematopoietic cells and has the ability to reactivate when triggered by immunological stress. This reactivation causes significant morbidity and mortality in immune-deficient patients, who are unable to control viral dissemination. While a competent immune system helps prevent clinically detectable viremia, a portrait of the factors that induce reactivation following the proper cues remains incomplete. Our understanding of the complex molecular mechanisms underlying latency and reactivation continue to evolve. We previously showed the HCMV-encoded G-protein coupled receptor US28 is expressed during latency and facilitates latent infection by attenuating the activator protein-1 (AP-1) transcription factor subunit, c-fos, expression and activity. We now show AP-1 is a critical component for HCMV reactivation. Pharmacological inhibition of c-fos significantly attenuates viral reactivation. In agreement, infection with a virus in which we disrupted the proximal AP-1 binding site in the major immediate early (MIE) enhancer results in inefficient reactivation compared to wild type. Concomitantly, AP-1 recruitment to the MIE enhancer is significantly decreased following reactivation of the mutant virus. Further, AP-1 is critical for de-repression of MIE-driven transcripts and downstream early and late genes, while immediate early genes from other loci remain unaffected. Our data also reveal MIE transcripts driven from the MIE promoter, the distal promoter, and the internal promoter, iP2, are dependent upon AP-1 recruitment, while iP1-driven transcripts are AP-1-independent. Collectively, our data demonstrate AP-1 binding to and activation of the MIE enhancer is a key molecular process controlling reactivation from latency.Significance StatementHuman cytomegalovirus (HCMV) is a common pathogen that infects the majority of the population for life. This infection poses little threat in immunologically healthy individuals, but can be fatal in people with compromised immune systems. Our understanding of the mechanisms underlying latency and reactivation remains incomplete. Here, we show the cellular transcription factor, AP-1, is a key to regulating HCMV reactivation. Our findings reveal AP-1 binding to the major immediate early enhancer/promoter is critical for switching this locus from one that is repressed during latency to one that is highly active following reactivation. Our work provides a novel mechanism HCMV exploits to reactivate, highlighting AP-1 as a potential target to prevent HCMV reactivation.

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“…The Flpe expression plasmid (pCSFLPe) was the kind gift of Dr. Gerhart Ryffel (Addgene plasmid #31130). pcDNA-BZLF1, pcDNA-gB and pcDNA-BMRF1 were previously described [41–43].…”

Section: Methodsmentioning

confidence: 99%

Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection

Inagaki

Sato

Ito

et al. 2020

Preprint

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36 Viral infection induces dynamic changes in transcriptional profiles. Virus-37 induced and anti-viral responses are intertwined during the infection. Epstein-38 Barr virus (EBV) is a human gammaherpesvirus that provides a model of 39 herpesvirus latency. To measure the transcriptome changes during the 40 establishment of EBV latency, EBV-negative Akata cells were infected with 41 EBV-EGFP and observed by transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 42 10, and 14 days after infection. We found transient downregulation of mitotic 43 division-related genes, reflecting reprograming of cell growth by EBV. Moreover, 44 a burst of viral lytic gene expression was detected in the early phase of 45 infection. Experimental and mathematical investigations demonstrated that 46 infectious virions were not produced in the pre-latent phase, suggesting the 47 presence of an abortive lytic infection. Finally, we conducted fate mapping using 48 recombinant EBV, enabling the noninvasive, continuous observation of infected 49 cells during EBV infection. Our tracking analysis provided direct evidence that 50 the abortive lytic infection in the pre-latent phase converges to latent infection 51 during EBV infection of B-cells, shedding light on novel roles of viral lytic 52 gene(s) in establishing latency. 53 54 Author summary 55Viral infection is a complex process that activates both virus-triggered and 56 host anti-viral responses. This process has classically been studied by snapshot 57 analysis such as microarray and RNA-seq at discrete time points as population 58 averages. Snapshot data lead to invaluable findings in host-pathogen 59 interactions. However, these "snapshot" omics, even from a single cell, lack 60 temporal resolution. Because the behavior of infected cells is highly dynamic 61 and heterogenous, continuous analysis is required for deciphering the fate of 62 infected cells during viral infection. Here, we exploited fate mapping techniques 63 with recombinant Epstein-Barr virus (EBV) to track the infected cells and 64 recorded a log of lytic gene expression during EBV infection. Our continuous 65 observation of infected cells revealed that EBV established latency in B-cells via 66 an abortive lytic infection in the pre-latent phase. 67 PubMed PMID: 19553389. 595

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BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon De Novo Infection

Cited by 30 publications

References 46 publications

Epstein‐Barr virus tegument protein BGLF2 inhibits NF‐κB activity by preventing p65 Ser536 phosphorylation

Epstein‐Barr virus tegument protein BGLF2 inhibits NF‐κB activity by preventing p65 Ser536 phosphorylation

Activator protein-1 transactivation of the major immediate early locus is a determinant of cytomegalovirus reactivation from latency

Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection

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