Epstein–Barr Virus: How Its Lytic Phase Contributes to Oncogenesis

The nuclear envelope (NE) of eukaryotic cells has a highly structural architecture, comprising double lipid-bilayer membranes, nuclear pore complexes, and an underlying nuclear lamina network. The NE structure is held in place through the membrane-bound LINC (linker of nucleoskeleton and cytoskeleton) complex, spanning the inner and outer nuclear membranes. The NE functions as a barrier between the nucleus and cytoplasm and as a transverse scaffold for various cellular processes. Epstein–Barr virus (EBV) is a human pathogen that infects most of the world’s population and is associated with several well-known malignancies. Within the nucleus, the replicated viral DNA is packaged into capsids, which subsequently egress from the nucleus into the cytoplasm for tegumentation and final envelopment. There is increasing evidence that viral lytic gene expression or replication contributes to the pathogenesis of EBV. Various EBV lytic proteins regulate and modulate the nuclear envelope structure in different ways, especially the viral BGLF4 kinase and the nuclear egress complex BFRF1/BFRF2. From the aspects of nuclear membrane structure, viral components, and fundamental nucleocytoplasmic transport controls, this review summarizes our findings and recently updated information on NE structure modification and NE-related cellular processes mediated by EBV.

Section: Overview Of Ebv Lytic Replicationmentioning

confidence: 99%

Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

Lee

Chen

2021

“…Indeed, the reasons for EBV’s ability to differentially reactivate under different conditions has been a long-standing question with relevance also to several diseases, including transplant- and other immunosuppression-related lymphoproliferative diseases and lymphomas. On the one hand, with the lytic phase playing an essential role in development of lymphoid and epithelial EBV cancers [ 3 , 4 ], such tumors could be prevented by blocking lytic activation. On the other, shifting the balance towards the lytic phase, thereby eliminating the residual subpopulation of the refractory cells, would be a tremendous boost to oncolytic therapies in which latently infected malignant cells are targeted for killing by induction of the viral lytic phase.…”

Section: A Two-population Problemmentioning

confidence: 99%

Inflammasome, the Constitutive Heterochromatin Machinery, and Replication of an Oncogenic Herpesvirus

Bhaduri‐McIntosh

McIntosh

2021

The success of long-term host–virus partnerships is predicated on the ability of the host to limit the destructive potential of the virus and the virus’s skill in manipulating its host to persist undetected yet replicate efficiently when needed. By mastering such skills, herpesviruses persist silently in their hosts, though perturbations in this host–virus equilibrium can result in disease. The heterochromatin machinery that tightly regulates endogenous retroviral elements and pericentromeric repeats also silences invading genomes of alpha-, beta-, and gammaherpesviruses. That said, how these viruses disrupt this constitutive heterochromatin machinery to replicate and spread, particularly in response to disparate lytic triggers, is unclear. Here, we review how the cancer-causing gammaherpesvirus Epstein–Barr virus (EBV) uses the inflammasome as a security system to alert itself of threats to its cellular home as well as to flip the virus-encoded lytic switch, allowing it to replicate and escape in response to a variety of lytic triggers. EBV provides the first example of an infectious agent able to actively exploit the inflammasome to spark its replication. Revealing an unexpected link between the inflammasome and the epigenome, this further brings insights into how the heterochromatin machinery uses differential strategies to maintain the integrity of the cellular genome whilst guarding against invading pathogens. These recent insights into EBV biology and host–viral epigenetic regulation ultimately point to the NLRP3 inflammasome as an attractive target to thwart herpesvirus reactivation.

“…It establishes lytic infection in epithelial cells and B lymphocytes, but the predominant mode of infection is the latency in B lymphocytes. The EBV latent infection is a common cause for B cell malignancy, whereas abortive lytic infections are also associated with the EBV-related oncogenesis [ 149 , 150 ]. Tsai et al showed that in primary B lymphocytes, EBV DNA was localized next to the ND10 components, Daxx and ATRX [ 151 ], which may reflect the host attempt to silence the incoming genome.…”

Section: Dual Role Of Nd10 In γ-Herpesvirus Infectionmentioning

confidence: 99%

The Role of ND10 Nuclear Bodies in Herpesvirus Infection: A Frenemy for the Virus?

Fada

Reward

2021

Nuclear domains 10 (ND10), a.k.a. promyelocytic leukemia nuclear bodies (PML-NBs), are membraneless subnuclear domains that are highly dynamic in their protein composition in response to cellular cues. They are known to be involved in many key cellular processes including DNA damage response, transcription regulation, apoptosis, oncogenesis, and antiviral defenses. The diversity and dynamics of ND10 residents enable them to play seemingly opposite roles under different physiological conditions. Although the molecular mechanisms are not completely clear, the pro- and anti-cancer effects of ND10 have been well established in tumorigenesis. However, in herpesvirus research, until the recently emerged evidence of pro-viral contributions, ND10 nuclear bodies have been generally recognized as part of the intrinsic antiviral defenses that converge to the incoming viral DNA to inhibit the viral gene expression. In this review, we evaluate the newly discovered pro-infection influences of ND10 in various human herpesviruses and analyze their molecular foundation along with the traditional antiviral functions of ND10. We hope to shed light on the explicit role of ND10 in both the lytic and latent cycles of herpesvirus infection, which is imperative to the delineation of herpes pathogenesis and the development of prophylactic/therapeutic treatments for herpetic diseases.