The ESCRT Machinery Is Recruited by the Viral BFRF1 Protein to the Nucleus-Associated Membrane for the Maturation of Epstein-Barr Virus

Lee, Chung Pei; Liu, Po Ting; Kung, Hsiu‐Ni; Su, Mei Tzu; Chua, Huey Huey; Chang, Julia Yu Fong; Chang, Chou Wei; Tsai, Ching Hwa; Liu, Fu Tong; Chen, Mei‐Ru

doi:10.1371/journal.ppat.1002904

Cited by 106 publications

(127 citation statements)

References 61 publications

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“…This phenomenon is unique to BFRF1 and not to other herpesviral homologs that need to cooperate with their UL31 homologs to induce vesicles derived from the NE (3). For BFRF1 function, the cellular endosomal sorting complex required for transport (ESCRT) machinery, a major membrane scission pathway involved in multivesicular body biogenesis and cytokinesis, is exploited through the recruitment of the ESCRT adaptor protein Alix by BFRF1 (3). Correspondingly, inhibition of ESCRT machinery by RNA interference or the expression of dominant-negative proteins induced the accumulation of viral DNA and capsid proteins in the nuclei of EBV-reactivated cells.…”

mentioning

confidence: 87%

“…Expression of BFRF1 alone induces not only multiple nuclear membranes and cytoplasmic cisternal membrane structures, but also the redistribution of the inner nuclear membrane (INM) protein emerin. This phenomenon is unique to BFRF1 and not to other herpesviral homologs that need to cooperate with their UL31 homologs to induce vesicles derived from the NE (3). For BFRF1 function, the cellular endosomal sorting complex required for transport (ESCRT) machinery, a major membrane scission pathway involved in multivesicular body biogenesis and cytokinesis, is exploited through the recruitment of the ESCRT adaptor protein Alix by BFRF1 (3).…”

mentioning

confidence: 96%

“…EBV BFRF1 is a homolog of herpes simplex virus 1 (HSV-1) UL34 and plays a crucial role in regulating NE architecture and the primary egress of nucleocapsids (3). Expression of BFRF1 alone induces not only multiple nuclear membranes and cytoplasmic cisternal membrane structures, but also the redistribution of the inner nuclear membrane (INM) protein emerin.…”

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confidence: 99%

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The Ubiquitin Ligase Itch and Ubiquitination Regulate BFRF1-Mediated Nuclear Envelope Modification for Epstein-Barr Virus Maturation

Lee

Liu

Kung

et al. 2016

J Virol

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The cellular endosomal sorting complex required for transport (ESCRT) was recently found to mediate important morphogenesis processes at the nuclear envelope (NE). We previously showed that the Epstein-Barr virus (EBV) BFRF1 protein recruits the ESCRT-associated protein Alix to modulate NE structure and promote EBV nuclear egress. Here, we uncover new cellular factors and mechanisms involved in this process. BFRF1-induced NE vesicles are similar to those observed following EBV reactivation. BFRF1 is ubiquitinated, and elimination of possible ubiquitination by either lysine mutations or fusion of a deubiquitinase hampers NE-derived vesicle formation and virus maturation. While it interacts with multiple Nedd4-like ubiquitin ligases, BFRF1 preferentially binds Itch ligase. We show that Itch associates with Alix and BFRF1 and is required for BFRF1-induced NE vesicle formation. Our data demonstrate that Itch, ubiquitin, and Alix control the BFRF1-mediated modulation of the NE and EBV maturation, uncovering novel regulatory mechanisms of nuclear egress of viral nucleocapsids. IMPORTANCEThe nuclear envelope (NE) of eukaryotic cells not only serves as a transverse scaffold for cellular processes, but also as a natural barrier for most DNA viruses that assemble their nucleocapsids in the nucleus. Previously, we showed that the cellular endosomal sorting complex required for transport (ESCRT) machinery is required for the nuclear egress of EBV. Here, we further report the molecular interplay among viral BFRF1, the ESCRT adaptor Alix, and the ubiquitin ligase Itch. We found that BFRF1-induced NE vesicles are similar to those observed following EBV reactivation. The lysine residues and the ubiquitination of BFRF1 regulate the formation of BFRF1-induced NE-derived vesicles and EBV maturation. During the process, a ubiquitin ligase, Itch, preferably associates with BFRF1 and is required for BFRF1-induced NE vesicle formation. Therefore, our data indicate that Itch, ubiquitin, and Alix control the BFRF1-mediated modulation of the NE, suggesting novel regulatory mechanisms for ESCRT-mediated NE modulation. T he eukaryotic nuclear envelope (NE) is a specialized compartment composed of double lipid-bilayer membranes and an underlying proteinaceous lamina network and connected by membrane-integrating nuclear pore complexes (NPCs) that selectively regulate the nucleocytoplasmic transport of macromolecules. The NE not only provides an intact meshwork to protect the genome's integrity from cytoplasmic insults, but also serves as a natural barrier against most DNA viruses that replicate their genomes within the nucleus (1). DNA viruses thus evolve various strategies to modify the NE for efficient material transport and nuclear egress of viral nucleocapsids.Epstein-Barr virus (EBV) is a gammaherpesvirus that infects most of the human population. After primary infection, EBV becomes latent in resting B cells and can be reactivated periodically for lytic replication and virus shedding. During lytic infection, several EBV gene pr...

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confidence: 87%

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confidence: 96%

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The Ubiquitin Ligase Itch and Ubiquitination Regulate BFRF1-Mediated Nuclear Envelope Modification for Epstein-Barr Virus Maturation

Lee

Liu

Kung

et al. 2016

J Virol

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“…This mechanism would also be analogous to herpesvirus/Epstein-Barr virus and megaRNP nuclear egress 35 ; genetic and biochemical evidence supports a role for ESCRT-III/Vps4 in Epstein-Barr virus nuclear egress. 36 Interestingly, it has been proposed that a nuclear egress mechanism might be an appealing way to clear large toxic nuclear protein aggregates too big to diffuse through the NPC, 37 precisely what we expect to accumulate upon NPC misassembly.…”

Section: Potential Models Of Aberrant Assembly Clearancementioning

confidence: 91%

ESCRTs breach the nuclear border

Webster

Lusk

2015

Nucleus

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T he endosomal sorting complexes required for transport (ESCRT) are best known for their role in sorting ubiquitylated membrane proteins into endosomes. The most ancient component of the ESCRT machinery is ESCRT-III, which is capable of oligomerizing into a helical filament that drives the invagination and scission of membranes aided by the AAA ATPase, Vps4, in several additional subcellular contexts. Our recent study broadens the work of ESCRT-III by identifying its role in a quality control pathway at the nuclear envelope (NE) that ensures the normal biogenesis of nuclear pore complexes (NPCs). Here, we will elaborate on how we envision this mechanism to progress and incorporate ESCRT-III into an emerging model of nuclear pore formation. Moreover, we speculate there are additional roles for the ESCRT-III machinery at the NE that broadly function to ensure its integrity and the maintenance of the nuclear compartment.

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“…As mentioned, this may be owing to the proximity of herpes virus transcription with the ESCRT pathway as other cellular products enter via Bback fusion^ [31,117]. Epstein-Barr virus (EBV) and Kaposi's sarcoma herpes virus (KSHV) have been the most studied, owing to the role of exosomes in the propogation of EBV-and KSHV-associated cancers, including nasopharyngeal sarcomas and Kaposi's sarcoma, respectively.…”

Section: Epstein-barr Virusmentioning

confidence: 99%

The Role of HTLV-1 in Alteration of Immune Regulation Through Regulatory T Cell Dysfunction and Exosomal Manipulation

Anderson

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The ESCRT Machinery Is Recruited by the Viral BFRF1 Protein to the Nucleus-Associated Membrane for the Maturation of Epstein-Barr Virus

Cited by 106 publications

References 61 publications

The Ubiquitin Ligase Itch and Ubiquitination Regulate BFRF1-Mediated Nuclear Envelope Modification for Epstein-Barr Virus Maturation

The Ubiquitin Ligase Itch and Ubiquitination Regulate BFRF1-Mediated Nuclear Envelope Modification for Epstein-Barr Virus Maturation

ESCRTs breach the nuclear border

The Role of HTLV-1 in Alteration of Immune Regulation Through Regulatory T Cell Dysfunction and Exosomal Manipulation

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