Interaction of Epstein-Barr Virus Latent Membrane Protein 1 with SCFHOS/β-TrCP E3 Ubiquitin Ligase Regulates Extent of NF-κB Activation

Tang, Weixin; Pavlish, O; Spiegelman, Vladimir S.; Parkhitko, Andrey A.; Fuchs, Serge Y.

doi:10.1074/jbc.m307962200

Cited by 43 publications

(34 citation statements)

References 62 publications

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“…the inhibition in NF-B activation (40,68). Additionally, the NSP1 protein of the porcine rotavirus (RV) strain OSU was demonstrated to stabilize activated IB␣ by binding to and degrading ␤-TrCP (69).…”

Section: Discussionmentioning

confidence: 99%

“…Comparable phosphodegron-like (PDL) motifs were found in viral proteins that target the NF-B pathway by interfering with the ␤-TrCP function. The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) and the VACV A49 protein were shown to block the degradation of IB␣ by binding to ␤-TrCP (40,68). Mutagenesis analysis demonstrated that the PDL motifs of both proteins were required for i., the cells were incubated with 100 ng/ml RhTNF-␣ for the indicated times.…”

Section: Discussionmentioning

confidence: 99%

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The ORF61 Protein Encoded by Simian Varicella Virus and Varicella-Zoster Virus Inhibits NF-κB Signaling by Interfering with IκBα Degradation

Whitmer

Malouli

Uebelhoer

et al. 2015

J Virol

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Varicella-zoster virus (VZV) causes chickenpox upon primary infection and establishes latency in ganglia.Reactivation from latency causes herpes zoster, which may be complicated by postherpetic neuralgia. Innate immunity mediated by interferon and proinflammatory cytokines represents the first line of immune defense upon infection and reactivation. VZV is known to interfere with multiple innate immune signaling pathways, including the central transcription factor NF-B. However, the role of these inhibitory mechanisms in vivo is unknown. Simian varicella virus (SVV) infection of rhesus macaques recapitulates key aspects of VZV pathogenesis, and this model thus permits examination of the role of immune evasion mechanisms in vivo. Here, we compare SVV and VZV with respect to interference with NF-B activation. We demonstrate that both viruses prevent ubiquitination of the NF-B inhibitor IB␣, whereas SVV additionally prevents IB␣ phosphorylation. We show that the ORF61 proteins of VZV and SVV are sufficient to prevent IB␣ ubiquitination upon ectopic expression. We further demonstrate that SVV ORF61 interacts with ␤-TrCP, a subunit of the SCF ubiquitin ligase complex that mediates the degradation of IB␣. This interaction seems to inactivate SCF-mediated protein degradation in general, since the unrelated ␤-TrCP target Snail is also stabilized by ORF61. In addition to ORF61, SVV seems to encode additional inhibitors of the NF-B pathway, since SVV with ORF61 deleted still prevented IB␣ phosphorylation and degradation. Taken together, our data demonstrate that SVV interferes with tumor necrosis factor alpha (TNF-␣)-induced NF-B activation at multiple levels, which is consistent with the importance of these countermechanisms for varicella virus infection. IMPORTANCEThe role of innate immunity during the establishment of primary infection, latency, and reactivation by varicella-zoster virus (VZV) is incompletely understood. Since infection of rhesus macaques by simian varicella virus (SVV) is used as an animal model of VZV infection, we characterized the molecular mechanism by which SVV interferes with innate immune activation. Specifically, we studied how SVV prevents activation of the transcription factor NF-B, a central factor in eliciting proinflammatory responses. The identification of molecular mechanisms that counteract innate immunity might ultimately lead to better vaccines and treatments for VZV, since overcoming these mechanisms, either by small-molecule inhibition or by genetic modification of vaccine strains, is expected to reduce the pathogenic potential of VZV. Moreover, using SVV infection of rhesus macaques, it will be possible to study how increasing the vulnerability of varicella viruses to innate immunity will impact viral pathogenesis. V aricella-zoster virus (VZV) is a member of the subfamily Alphaherpesvirinae and is the causative agent of chickenpox and herpes zoster (HZ). Following primary infection, VZV establishes latency in ganglia. Reactivation from latency, which typically occurs late...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The ORF61 Protein Encoded by Simian Varicella Virus and Varicella-Zoster Virus Inhibits NF-κB Signaling by Interfering with IκBα Degradation

Whitmer

Malouli

Uebelhoer

et al. 2015

J Virol

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“…β-TrCP1 interacts with HIV-1 Vpu and regulates HIV release by mediating the degradation of its substrates. Additionally, Tang et al found that the EBV LMP1-95-8 variant reduced the levels of endogenous β-TrCP2/HOS via phosphorylated IBα, suggesting that LMP1-95-8 is a pseudo-substrate of the SCFβ-TrCP/HOS E3 ubiquitin ligase and that interaction between LMP1 and HOS restricts the extent of LMP1-induced NF-B signaling [64].…”

Section: Discussionmentioning

confidence: 99%

Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas

Zeng

Huang

et al. 2014

Sci. China Life Sci.

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Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC) tumorigenesis. However, the mechanism(s) connecting EBV infection and NPC remain unclear. Recently, a new class of EBV microRNAs (miRNAs) has been described. To determine how EBV miRNAs control the expression of host genes, and to understand their potential role in NPC tumorigenesis, we profiled the expression of 44 mature EBV miRNAs and potential host genes in NPC and non-tumor nasopharyngeal epithelial tissues. We found that 40 EBV miRNAs from the BART transcript were highly expressed in NPC. Analysis of potential BART miRNA target genes revealed that 3140 genes and several important pathways might be involved in the carcinogenesis of NPC. A total of 105 genes with potential EBV miRNA binding sites were significantly downregulated, suggesting that EBV miRNAs may regulate these genes and contribute to NPC carcinogenesis. An EBV miRNA and host gene regulation network was generated to provide useful clues for validating of EBV miRNA functions in NPC tumorigenesis.

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“…Ранее показано, что функциональное значение некоторых встречающихся мутаций (I85L, F106Y, E328Q, S366T), проявляется в снижении цитотоксичности и усилении трансформирующей активности белка LMP1 [15,29]. Другие точечные мутации, обнаруженные нами в исследуемых вариантах (D210E, G352S, W39C, L93V, A96T, I122L, S239M), ранее не описаны, однако некоторые из них локализуются вблизи функциональных доменов LMP1 и, возможно, могут оказывать влияние на свойства этой молекулы.…”

Section: результатыиобсуждениеunclassified

“…Активность транскрипционных факторов NF-kB и АP-1 определяли количественно по экспрессии люциферазы из репортерных плазмид kB-ConA-Luc и AP1-Luc, котрансфецированных в клетки HEK293 вместе с векторными конструкциями, содержащими полноразмерные варианты LMP1 [29]. Через 24 ч после трансфекции клетки отмывали в PBS и лизировали в 1´RLB буфере ("Promega").…”

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Functional analysis of epstein-barr virus latent membrane proteins (LMP1) in patients with limphoproliferative disorders

2011

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Latent membrane protein1 (LMP1) encoded by the LMP1 gene of the Epstein-Barr virus (EBV) is a transmembrane protein, which can activate a number of cellular signal cascades and transcriptional factors leading to cell transformation. In the present study the sequencing of full-length LMP1 variants isolated from Russian patients with Hodgkin's lymphoma (HL), non-Hodgkin's lymphomaе (NHL) and infectious mononucleosis (IM) has been carried out. The phylogenetic analysis of obtained sequences revealed dominance of the LMP1 variants belonging to proteins of low-divergent group LMP1-B95.8b characterized by minimal set of mutations. Investigation of biological properties in the Russian representatives of this group revealed that expression of studied LMP1 variants in embryonic kidney 293 cells was accompanied by insignificant increase in transcriptional factor NF-κB activation and had minor influence on activation of transcriptional factor AP-1. It was also detected that all investigated low-divergent LMP1 variants expressed in Rat-1 cells induced activation of inducible NO-synthase (iNOS) and intracellular production of nitric oxide (NO). At the same time the level of NO accumulation was lower than that induced by the low-transforming prototype variant LMP1-B95.8. The data obtained indicate that the LMP1 variants, which are the most common among Russian patients with EBV-associated lymphoproliferative diseases, are characterized by minimum number of mutations and rather low ability to activate basic cellular signaling pathways regardless the nature of pathological process, benign (IM) or malignant (HL, NHL). It is suggested that in addition to the modest activation of NF-κB and iNOS induction by LMP1 other factors are involved in the cell transformation process.

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Interaction of Epstein-Barr Virus Latent Membrane Protein 1 with SCFHOS/β-TrCP E3 Ubiquitin Ligase Regulates Extent of NF-κB Activation

Cited by 43 publications

References 62 publications

The ORF61 Protein Encoded by Simian Varicella Virus and Varicella-Zoster Virus Inhibits NF-κB Signaling by Interfering with IκBα Degradation

The ORF61 Protein Encoded by Simian Varicella Virus and Varicella-Zoster Virus Inhibits NF-κB Signaling by Interfering with IκBα Degradation

Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas

Functional analysis of epstein-barr virus latent membrane proteins (LMP1) in patients with limphoproliferative disorders

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