EBV Reactivation from Latency Is a Degrading Experience for the Host

Casco, Alejandro; Johannsen, Eric

doi:10.3390/v15030726

Cited by 6 publications

(11 citation statements)

References 73 publications

(131 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Why might BALF0/1 protein level targeting of BCR complexes be necessary in cells that also express the EBV alkaline nuclease BGLF5, which exerts host shutoff function beginning in the early lytic period (15)? First, immunoglobulin mRNA is highly abundant in B-cells, and a subset of BCR-encoding transcripts likely evades host shut-off.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Yiu,

Weekes,

Gewurz

2024

Preprint

View full text Add to dashboard Cite

Epstein–Barr virus (EBV) establishes persistent infection, causes infectious mononucleosis, is a major trigger for multiple sclerosis and contributes to multiple cancers. Yet, knowledge remains incomplete about how the virus remodels host B cells to support lytic replication. We previously identified that EBV lytic replication results in selective depletion of plasma membrane B-cell receptor (BCR) complexes, comprised of immunoglobulin and the CD79A and CD79B signaling chains. Here, we used proteomic and biochemical approaches to identify that the EBV early lytic protein BALF0/1 is responsible for EBV lytic cycle BCR degradation. Mechanistically, an immunoglobulin heavy chain cytoplasmic tail KVK motif was required for ubiquitin-mediated BCR degradation, while CD79A and CD79B were dispensable. BALF0/1 subverted caveolin-mediated endocytosis to internalize plasma membrane BCR complexes and to deliver them to the endoplasmic reticulum. BALF0/1 stimulated immunoglobulin heavy chain cytoplasmic tail ubiquitination, which together with the ATPase valosin-containing protein/p97 drove ER-associated degradation of BCR complexes by cytoplasmic proteasomes. BALF0/1 knockout reduced the viral load of secreted EBV particles from B-cells that expressed a monoclonal antibody against EBV glycoprotein 350 and increased viral particle immunoglobulin incorporation. Consistent with downmodulation of plasma membrane BCR, BALF0/1 overexpression reduced viability of a diffuse large B-cell lymphoma cell line dependent upon BCR signaling. Collectively, our results suggest that EBV BALF0/1 downmodulates immunoglobulin upon lytic reactivation to block BCR signaling and support virion release.SIGNIFICANCEEBV uses a biphasic lifecycle, in which it switches between a latent state that facilitates immune evasion and a lytic state, where virion are secreted. However, when EBV infects a B-cell that makes antibody against a virion protein, EBV must have a strategy to escape becoming trapped, since maturing virion and antibody each traffic through the secretory pathway. We identified that an EBV-encoded protein expressed, BALF0/1, associates with and targets immunoglobulin complexes for degradation. Intriguingly, BALF0/1 subverts the caveolin-1 and ERAD pathways to route antibody from the plasma membrane to cytoplasmic proteasomes for degradation. We present evidence that this enhances EBV secretion from cells that produce antibody against a viral glycoprotein, which could otherwise trap virus.

show abstract

Section: Discussionmentioning

confidence: 99%

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Yiu,

Weekes,

Gewurz

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The three main EBV proteins that enable this evasion are early lytic cycle proteins, BGLF5, BNLF2a and BILF1 [ 68 ]. The BGLF5 protein interferes with T cell recognition via the promotion of HLA I-encoded mRNA degradation, but it is not potent enough to completely impair it, unlike the other two proteins, BNLF2a and BILF1 [ 69 ]. For instance, BNLF2a is a vital EBV inhibitor of the transporter associated with antigen processing (TAP) protein complex.…”

Section: Specific Immune Response To Ebvmentioning

confidence: 99%

Deciphering the Role of Epstein–Barr Virus Latent Membrane Protein 1 in Immune Modulation: A Multifaced Signalling Perspective

Šimičić,

Batović,

Stojanović Marković

et al. 2024

Viruses

View full text Add to dashboard Cite

The disruption of antiviral sensors and the evasion of immune defences by various tactics are hallmarks of EBV infection. One of the EBV latent gene products, LMP1, was shown to induce the activation of signalling pathways, such as NF-κB, MAPK (JNK, ERK1/2, p38), JAK/STAT and PI3K/Akt, via three subdomains of its C-terminal domain, regulating the expression of several cytokines responsible for modulation of the immune response and therefore promoting viral persistence. The aim of this review is to summarise the current knowledge on the EBV-mediated induction of immunomodulatory molecules by the activation of signal transduction pathways with a particular focus on LMP1-mediated mechanisms. A more detailed understanding of the cytokine biology molecular landscape in EBV infections could contribute to the more complete understanding of diseases associated with this virus.

show abstract

“…Type II ROCC leads to the cellular chromatin being condensed to the nuclear periphery, adjacent to the nuclear lamina [ 7 , 15 ]. It is likely that this localization leads to an increase in repression of cellular transcription, favoring the transcription of viral genes, thus contributing to virus-mediated host shutoff [ 101 ]. An analysis of both cellular and viral transcription during the early phase of the lytic cycle of EBV supports this conclusion; the expression of 99% of cellular genes on average was inhibited 3-fold, while that of some viral genes was increased 100-fold or more [ 102 ].…”

Section: Why Might Viruses Trigger Chromatin Reorganization?mentioning

confidence: 99%

Five families of diverse DNA viruses comprehensively restructure the nucleus

Rosemarie,

Sugden

2023

PLoS Biol

View full text Add to dashboard Cite

Many viruses have evolved ways to restructure their host cell’s nucleus profoundly and unexpectedly upon infection. In particular, DNA viruses that need to commandeer their host’s cellular synthetic functions to produce their progeny can induce the condensation and margination of host chromatin during productive infection, a phenomenon known as virus-induced reorganization of cellular chromatin (ROCC). These ROCC-inducing DNA viruses belong to 5 families (herpesviruses, baculoviruses, adenoviruses, parvoviruses, and geminiviruses) that infect a wide range of hosts and are important for human and ecosystem health, as well as for biotechnology. Although the study of virus-induced ROCC is in its infancy, investigations are already raising important questions, such as why only some DNA viruses that replicate their genomes in the nucleus elicit ROCC. Studying the shared and distinct properties of ROCC-inducing viruses will provide valuable insights into viral reorganization of host chromatin that could have implications for future therapies that target the viral life cycle.

show abstract

EBV Reactivation from Latency Is a Degrading Experience for the Host

Cited by 6 publications

References 73 publications

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Deciphering the Role of Epstein–Barr Virus Latent Membrane Protein 1 in Immune Modulation: A Multifaced Signalling Perspective

Five families of diverse DNA viruses comprehensively restructure the nucleus

Contact Info

Product

Resources

About