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Review
. 2024 Jan 25;16(2):183.
doi: 10.3390/v16020183.

Epigenetic Restriction Factors (eRFs) in Virus Infection

Arunava Roy  1 , Anandita Ghosh  1
Affiliations
Review

Epigenetic Restriction Factors (eRFs) in Virus Infection

Arunava Roy et al. Viruses. .

Abstract

The ongoing arms race between viruses and their hosts is constantly evolving. One of the ways in which cells defend themselves against invading viruses is by using restriction factors (RFs), which are cell-intrinsic antiviral mechanisms that block viral replication and transcription. Recent research has identified a specific group of RFs that belong to the cellular epigenetic machinery and are able to restrict the gene expression of certain viruses. These RFs can be referred to as epigenetic restriction factors or eRFs. In this review, eRFs have been classified into two categories. The first category includes eRFs that target viral chromatin. So far, the identified eRFs in this category include the PML-NBs, the KRAB/KAP1 complex, IFI16, and the HUSH complex. The second category includes eRFs that target viral RNA or, more specifically, the viral epitranscriptome. These epitranscriptomic eRFs have been further classified into two types: those that edit RNA bases-adenosine deaminase acting on RNA (ADAR) and pseudouridine synthases (PUS), and those that covalently modify viral RNA-the N6-methyladenosine (m6A) writers, readers, and erasers. We delve into the molecular machinery of eRFs, their role in limiting various viruses, and the mechanisms by which viruses have evolved to counteract them. We also examine the crosstalk between different eRFs, including the common effectors that connect them. Finally, we explore the potential for new discoveries in the realm of epigenetic networks that restrict viral gene expression, as well as the future research directions in this area.

Keywords: ADAR; HUSH complex; IFI16; KRAB/KAP1; N6 methyl adenosine (m6A); PML-NB; epigenetic viral restriction factor (eRF); epitranscriptomics; pseudouridine synthases (PUS); viral chromatin.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Four different chromatin-targeting eRFs have been identified to date. These are the PML-NBs, the KRAB ZNF/KAP1 complex, the IFI16, and the HUSH complex. These eRFs recruit other epigenetic modifiers that help recruit repressive histone marks like H3K9me3 on the genomes of target viruses. This results in heterochromatinization of the viral chromatin, making them more compact and inaccessible to RNA polymerases and other transcriptional machineries. Each of these eRFs has been reported to epigenetically restrict several different viruses in the literature (denoted in green). Additionally, some viruses have developed strong antagonistic mechanisms to prevent the activity of eRFs during infection or reactivation from latency. These antagonistic viral proteins are illustrated in red. The chromatin in blue denotes viral genomes, either episomal or integrated. Illustration created with BioRender.com.
Figure 2
Figure 2
Three epitranscriptomic systems have been identified to serve as antiviral restriction factors. Two among these, ADAR (adenosine deaminase acting on RNA) and PUS (pseudouridine synthases), are RNA-editing mechanisms that introduce mutations in the reading frame post-transcriptionally. The third, N6-methylasenosine writers (METTL3, METTL14, WTAP, and VIRMA), readers, and erasers, together modify viral RNA and determine its intracellular fate. Each of these epitranscriptomic eRFs has been reported to restrict several viruses in the literature (denoted in green). Adenovirus (AdV) virus-associated RNA-1 (VAI) functions as a potent inhibitor of ADAR1 but not ADAR2. Considering the fact that neither the VAI nor any other AdV mRNA is a substrate for ADAR1, the function of this antagonism is unknown. Illustration created with BioRender.com.
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