Identification of Epstein-Barr Virus Replication Proteins in Burkitt’s Lymphoma Cells

Traylen, Chris; Ramasubramanyan, Sharada; Zuo, Jianmin; Rowe, Martin; Almohammad, Rajaei; Heesom, Kate J; Sweet, Steve M. M.; Matthews, David A.; Sinclair, Alison J.

doi:10.3390/pathogens4040739

Cited by 18 publications

(18 citation statements)

References 43 publications

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“…This premise is supported by data from in vitro studies as well as studies using SCID and humanized mouse models [128,129,130,131]. Similar results have also been reported for Burkitt’s lymphoma [132]. Likewise, HHV-8 associated tumors exhibit low levels of virus reactivation and epidemiological studies support the premise that lytic/abortive-lytic replication is important in the initiation and progression of these tumors [133,134].…”

Section: Herpesviruses Dutpases and Human Diseasesupporting

confidence: 64%

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease

2016

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The human herpesviruses are ubiquitous viruses and have a prevalence of over 90% in the adult population. Following a primary infection they establish latency and can be reactivated over a person’s lifetime. While it is well accepted that human herpesviruses are implicated in numerous diseases ranging from dermatological and autoimmune disease to cancer, the role of lytic proteins in the pathophysiology of herpesvirus-associated diseases remains largely understudies. Only recently have we begun to appreciate the importance of lytic proteins produced during reactivation of the virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase), as key modulators of the host innate and adaptive immune responses. In this review, we provide evidence from animal and human studies of the Epstein–Barr virus as a prototype, supporting the notion that herpesviruses dUTPases are a family of proteins with unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer.

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Section: Herpesviruses Dutpases and Human Diseasesupporting

confidence: 64%

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease

2016

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“…The mechanism remains unknown. BGLF4 was proposed to phosphorylate BGLF5 by an in vitro screen [38], but this finding was not confirmed by mass spectrometry analysis of phosphorylated EBV proteins in Burkitt's lymphoma cells [39]. Also, it is not clear whether the BGLF5 homologs SOX and muSOX are also regulated by the homologous KSHV and MHV68 kinases.…”

Section: Modulation Of Host Shutoff Activity By Other Viral Proteinsmentioning

confidence: 98%

Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

2020

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The evolutionary arms race between host and pathogen has resulted in the ability of many human viruses to alter the host gene expression profile during infection, in order to redirect cellular resources towards viral gene expression and inhibit cell-intrinsic host immune responses. In particular, multiple viruses globally reduce host gene expression in a process termed "host shutoff." Multiple mechanisms of host shutoff exist, including translational and transcriptional shutoff, but several viruses carry out host shutoff by encoding ribonucleases (RNases) that degrade host messenger RNAs (mRNAs). Viral host shutoff RNases include the influenza A virus polymerase acidic-X (PA-X) [1], the herpes simplex viruses (HSV-1 and -2) virion host shutoff protein (vhs) [2], and the Kaposi's sarcoma-associated herpesvirus (KSHV) shutoff and exonuclease (SOX) protein [3] and its homologs, muSOX from murine gammaherpesvirus 68 (MHV68) [4] and BGLF5 from Epstein-Barr virus (EBV) [5]. These RNases contribute to efficient formation of virions and/or reduction of innate immune signaling [6][7][8]. For example, in the absence of EBV BGLF5, the virus produces fewer mature capsids, many of which remain trapped in the nucleus [7]. Vhs-deficient HSV replicates well in many common tissue culture models [9] but shows replication defects in relevant cell types, such as cerebellar granule neurons [8]. Moreover, in mice, viruses lacking detectable host shutoff activity replicate to lower viral titers in neuronal tissue [9], indicating a restriction of viral replication probably related to host immune responses. Influenza A virus PA-X also limits host antiviral and proinflammatory responses in several animal models [1,10,11] but has minimal effect on viral replication both in vivo and in cell culture [1,11,12]. Although host shutoff RNases are important for successful viral infection, their activity presents an interesting problem for the viruses that encode them. Unregulated RNase activity could degrade viral RNAs or host mRNAs encoding proteins that the virus needs. Moreover, drastic depletion of the mRNA pool by the virus could trigger antiviral host stress responses and cell death. It is thus unsurprising that evidence is now emerging that viruses posttranslationally regulate the activity of their host shutoff RNases through a variety of mechanisms, reviewed herein (Fig 1), to finetune host gene regulation without inhibiting viral replication. Selection of targeted and protected RNAs and protein/protein interactionsAll host shutoff RNases cause global decreases in host mRNA abundance, revealed by transcriptome-wide studies [13][14][15], and display a preference for mRNAs while sparing housekeeping noncoding RNAs (ncRNAs) [12,16,17]. However, host shutoff RNases are less PLOS PATHOGENS PLOS Pathogens | https://doi.

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“…All in all, these studies investigating serological lytic EBV markers have emphasized the prominent role importance of the lytic infection in EBV malignancies. Recently, the identification by mass spectrometry of 44 different EBV proteins in Burkitt lymphoma cells undergoing EBV replication has increased the knowledge base on EBV lytic replication, possibly highlighting different targets for future therapeutic strategies [40].…”

Section: Arguments Of the Pathogenic Role Of Lytic Infection In Ebv-amentioning

confidence: 99%

“…Many articles have previously mentioned the existence of the lytic cycle, especially in transplant patients with PTLD. Studies conducted on EBV lytic proteins, especially the IE proteins like ZEBRA, in patients with PTLD or HIV-associated NHL are still scarce, mostly relating to the role of EBV proteins and gene products in neoplastic tissues [18,40,[90][91][92][93][94][95]. It must be pointed out that several authors exploring BZLF1 transcripts in the peripheral blood lymphocytes (PBL) of PTLD patients demonstrated that both a high EBV genome number and strong BZLF1 mRNA expression are sensitive markers of EBV-related PTLD [96].…”

Section: Consequences In Terms Of Diagnosis and Therapymentioning

confidence: 99%

The Role of the Epstein-Barr Virus Lytic Cycle in Tumor Progression: Consequences in Diagnosis and Therapy

Drouet¹

2020

Human Herpesvirus Infection - Biological Features, Transmission, Symptoms, Diagnosis and Treatment

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The Epstein-Barr virus (EBV) reactivation corresponds to the activation of EBV global replication involving not only the origin of the latent viral replication but also that of the origin of lytic replication. During this reactivation, a minority of B cells infected with EBV in its latent form enter the lytic phase. During this phase, all EBV proteins are produced, enabling the assembly of complete virions that lysate their host cells and infect neighboring cells (lytic cycle). This horizontal EBV transmission seeks to increase the pool of EBV-infected B cells. This chapter seeks to review the role of the lytic EBV proteins (particularly that of the ZEBRA protein) in tumor development. This protein is the main transcription factor of EBV, expressed during the activation of the lytic cycle. Recently, we demonstrated that this immediate early protein can be detected in the soluble state (s-ZEBRA) in the serum of patients with posttransplant lymphoproliferative disorder. We highlighted the role of ZEBRA in EBV pathogenesis in transplanted subjects, not only as a key protein in the activation of EBV replication but also as a protein "toxoid" released into the extracellular milieu. This release could result in increased secretion of immunomodulatory cytokines and that of angiogenesis-promoting factors conducive to tumor progression.

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Identification of Epstein-Barr Virus Replication Proteins in Burkitt’s Lymphoma Cells

Cited by 18 publications

References 43 publications

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease

Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

The Role of the Epstein-Barr Virus Lytic Cycle in Tumor Progression: Consequences in Diagnosis and Therapy

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