Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

Abstract

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.

‘Come together’—The Regulatory Interaction of Herpesviral Nuclear Egress Proteins Comprises Both Essential and Accessory Functions

“…Since the diameter of herpesviral capsids is approximately 130 nm [ 1 ], herpesviruses have emerged as a specific mechanism, the so-called regulated nuclear egress, to bypass this barrier in a finely coordinated manner ( Figure 1 ). Thus, the nuclear egress is a crucial step during the late phase of replication and is conserved among α-, β- and γ-herpesviruses [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…As a characteristic feature of herpesviruses, the viral nuclear egress is a highly coordinated, multistep regulatory process. In this regard, the herpesviral NEC is a fascinating example of how a viral heterodimeric element (i.e., the core NEC) can provide a scaffold that hijacks host-specific functions including protein transport and intracellular trafficking [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 16 ]. Considering the specific case of HCMV, a central mechanistic determinant of nuclear egress is given by the multi-interacting pUL50, which is anchored to the nuclear membrane through its transmembrane domain (TMD).…”

Epstein–Barr Virus Infection in Lung Cancer: Insights and Perspectives

“…After viral attachment, entry occurs by cell fusion, allowing the entry of the tegumented capsid into the cytoplasm [36]. Next, the capsid with the genome is transported to the periphery of the nucleus [37] and the viral genome crosses the nuclear pore complexes to enter the nucleus [38]. The Epstein-Barr nuclear antigen 1 (EBNA1) gene is expressed, leading to the EBV genome tethering to the host genome and is maintained as an episome [39,40].…”

“…The synthetized linear EBV genome is cleaved at the terminal repeats and packaged into viral capsids. The serine/threonine-protein kinase BFRF1 and BFLF2 genes allow intranuclear nucleocapsids to move towards the inner leaflet of the nuclear membrane and sprout from the nuclear envelope [38]. Next, the access of nucleocapsids to the nuclear membrane is mediated by the viral BGLF4 protein [38].…”

“…The serine/threonine-protein kinase BFRF1 and BFLF2 genes allow intranuclear nucleocapsids to move towards the inner leaflet of the nuclear membrane and sprout from the nuclear envelope [38]. Next, the access of nucleocapsids to the nuclear membrane is mediated by the viral BGLF4 protein [38]. The nucleocapsids can then be transported into the juxtanuclear viral assembly compartment.…”