Mono a Mano: ZBP1’s Love–Hate Relationship with the Kissing Virus

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.

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

“…However, the efficient elimination of EBV is difficult because of the EBV latency after the initial infection. A new hypothesis holds that ZBP1 is not involved in EBV’s lysis replication but is contribute to the EBV latency [ 107 ]. There are two possible pathways by that ZBP1 induces the establishment and maintenance of EBV latency and both depends on suppressive dimethylation of the histone H3 lysine 9 residue (H3K9me2) [ 107 ].…”

“…A new hypothesis holds that ZBP1 is not involved in EBV’s lysis replication but is contribute to the EBV latency [ 107 ]. There are two possible pathways by that ZBP1 induces the establishment and maintenance of EBV latency and both depends on suppressive dimethylation of the histone H3 lysine 9 residue (H3K9me2) [ 107 ]. The first pathway, ZBP1 senses and binds to the strong Z-DNA prone sequences in multiple promoter regions of the EBV genome, then further locates C-terminal binding protein (CTBP) to the Z-sequences within promoters could induce H3K9 methylation by MYC oncogene protein [ 107 , 108 ].…”

“…There are two possible pathways by that ZBP1 induces the establishment and maintenance of EBV latency and both depends on suppressive dimethylation of the histone H3 lysine 9 residue (H3K9me2) [ 107 ]. The first pathway, ZBP1 senses and binds to the strong Z-DNA prone sequences in multiple promoter regions of the EBV genome, then further locates C-terminal binding protein (CTBP) to the Z-sequences within promoters could induce H3K9 methylation by MYC oncogene protein [ 107 , 108 ]. The other pathway, EBV-produced Z-NA activates ZBP1-RIPK1-mediated NF-κB signaling during the initial stages of infection [ 16 ].…”

Z-RNA and the flipside of the SARS Nsp13 helicase

“…In the example of SARS2, the Z-forming potential of the SARS1 Nsp3 Z-sig is reduced by non-synonymous mutations, leaving the encoded peptide the same (Figure 3B). It is unknown whether this decrease in the potential to form Z-RNA increased the potential for SARS2 to become pandemic, but viruses like Epstein-Barr virus show selection against Z-DNA forming sequences relative to other HHVs [47].…”

Z-RNA and the Flipside of the SARS Nsp13 Helicase: Is There a Role for Flipons in Coronavirus-Induced Pathology?

“…It is unknown whether this decrease in the potential to form Z-RNA increased the potential for SARS-CoV2 to become pandemic, but viruses like Epstein-Barr virus show selection against Z-DNA forming sequences relative to other HHVs (50).…”