Mono a Mano: ZBP1's Love-Hate Relationship with the Kissing Virus
Alan Herbert1,2, Aleksandr Fedorov2, Maria Poptsova2
1InsideOutBio, 42 8th Street, Charlestown, MA 02129, USA.
Abstract:
Z-DNA binding protein (ZBP1) very much represents the nuclear option. By initiating inflammatory cell death (ICD), ZBP1 activates host defenses to destroy infectious threats. ZBP1 is also able to induce noninflammatory regulated cell death via apoptosis (RCD). ZBP1 senses the presence of left-handed Z-DNA and Z-RNA (ZNA), including that formed by expression of endogenous retroelements. Viruses such as the Epstein-Barr "kissing virus" inhibit ICD, RCD and other cell death signaling pathways to produce persistent infection. EBV undergoes lytic replication in plasma cells, which maintain detectable levels of basal ZBP1 expression, leading us to suggest a new role for ZBP1 in maintaining EBV latency, one of benefit for both host and virus. We provide an overview of the pathways that are involved in establishing latent infection, including those regulated by MYC and NF-κB. We describe and provide a synthesis of the evidence supporting a role for ZNA in these pathways, highlighting the positive and negative selection of ZNA forming sequences in the EBV genome that underscores the coadaptation of host and virus. Instead of a fight to the death, a state of détente now exists where persistent infection by the virus is tolerated by the host, while disease outcomes such as death, autoimmunity and cancer are minimized. Based on these new insights, we propose actionable therapeutic approaches to unhost EBV.
Insights
Z-DNA binding protein 1 (ZBP1) triggers cell death to fight infections but also aids Epstein-Barr virus (EBV) latency. This discovery suggests ZBP1 maintains a host-virus détente, minimizing disease.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Z-DNA binding protein 1 (ZBP1) is a key mediator of host defense, inducing inflammatory (ICD) and non-inflammatory (RCD) cell death pathways.
- ZBP1 recognizes left-handed Z-DNA and Z-RNA (ZNA) structures, which can arise from endogenous retroelements or viral infections.
- Epstein-Barr virus (EBV) employs strategies to evade ZBP1-mediated cell death, establishing persistent infections.
Purpose of the Study:
- To investigate the role of ZBP1 in Epstein-Barr virus (EBV) latency.
- To explore the interplay between ZNA formation, host cell pathways (MYC, NF-κB), and EBV genome evolution.
- To propose novel therapeutic strategies targeting EBV persistence.
Main Methods:
- Review and synthesis of existing literature on ZBP1, ZNA, EBV latency, and host-pathogen interactions.
- Analysis of evidence supporting the role of ZNA in EBV latency pathways.
- Identification of co-adapted sequences in the EBV genome related to ZNA formation.
Main Results:
- ZBP1, while inducing cell death against pathogens, may also facilitate EBV latency in plasma cells.
- ZNA formation and its regulation by host factors like MYC and NF-κB are implicated in EBV latency.
- EBV genome exhibits selection for ZNA-forming sequences, indicating host-virus co-adaptation.
Conclusions:
- ZBP1 plays a dual role in EBV infection, potentially benefiting both host and virus by establishing a state of controlled persistence.
- A détente exists between EBV and the host, mediated by ZBP1 and ZNA, which minimizes disease outcomes.
- Targeting ZBP1 and ZNA interactions offers potential therapeutic avenues for managing EBV persistence.
Related Concept Videos
01:33Coat Assembly and GTPases
Coat assembly depends on the local availability of phosphatidylinositol phosphates or PIPs and GTP-binding proteins. Adaptor proteins, which link the coat proteins to the membrane, bind to these PIPs and play a crucial role in controlling...
01:10Intracellular Movement of Viruses and Bacteria
02:28Leaky Scanning