Nature | the new coronavirus is directly related to epiregulation - the histone "mimicry" of the new coronavirus

Written by | November

One of the important reasons why the new coronavirus will be a global pandemic is that it can effectively inhibit the response of host cells [1-2].

Studies have found that viral proteins inhibit antiviral responses by mimicking key regions of human histones, and SARS-CoV-2 significantly disrupts the epigenetic regulation of host cells [3-5].

However, it is unclear how SARS-CoV-2 controls epigenetic modifications of host cell genomes
to inhibit the human antiviral response.

On October 5, 2022, the Erica Korb research group of the University of Pennsylvania issued an article entitled SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry, which found that there is histone "mimicry" in the new coronavirus protein, Thus disrupting the crown genetic regulation
of host cells.

To determine whether histone mimicry is present in the new coronavirus, the authors bioinformatically compared
all SARS-CoV-2 viral proteins with human histones.
The changes in the proteins encoded by ORF3b and ORF8 in the SARS-CoV-2 viral protein are quite
different from those of previous coronaviruses.
ORF8 has a similar motif to the N-terminal tail region of histone H3 (Figure 1).

This motif contains the ARKs sequence, which is considered one of the most critical regions of histone H3, has several different types of post-translational modifications, including H3K9me, H3K9ac, H3K27me, and H3K27ac
.
In addition, ORF8 is highly expressed during infection, and interactive proteomics studies have found that ORF8 interacts with DNA methyltransferase DNMT1
.
These results all suggest that ORF8 may have histone mimicry characteristics
.

Fig.
1 There is a histone H3-like motif in ORF8

To confirm this possibility, the authors first examined the localization
of ORF8 within cells.
Although ORF8 does not have a well-defined nuclear localization sequence, it is 15 kDa in size, so it is sufficient to spread into the
nucleus.
In addition, by co-immunostaining with nuclear membrane proteins, the authors found that ORF8 co-localized
with laminB and laminA/C.
To explore ORF8's role in regulating chromatin in the nucleus of host cells, the authors found that ORF8 binds
to chromatin.
Through ChIP-seq and co-immunoprecipitation, the authors found that ORF8 interacts
with laminB1, histone H3, and heterochromatin protein HP1α.
In addition, the authors found that ORF8 expression affected chromatin-related proteins in host cells, such as a significant decrease
in the abundance of histone acetyltransferase KAT2A after ORF8 expression.
Therefore, ORF8 has histone mimicry characteristics
in the host cell.

The authors then analyzed the role of the ARKS motif in the ORF8 region, which influences the modification of H3K9me3 and H3K27me3 and H3K9ac in host cells in a motif-dependent manner (Figure 2).

Infection of cells by SARS-CoV-2 leads to disruption of chromatin regulation in host cells, and knockout ORF8 attenuates this phenotype, and knocking out the ARKS motif alone can simulate the effect of
ORF8 knockout.
Therefore, ORF8, especially the key motifs contained in it, are involved in the effect of
SARS-CoV-2 infection on chromatin accessibility and histone modification in host cells.

Fig.
2 ORF8 affects the epigenetic modification of host cells in the manner since the ARKS motif

Finally, the authors wanted to know how the new coronavirus disrupts the epigenetics of host cells through histone mimicry and thus affects gene transcription, and found that the presence of ORF8 and histone mimicry motifs through experiments such as RNA-seq will change the transcriptional response of host cells to infection and will also affect the replication copy number
of the virus itself.

Figure 3 Working model

Overall, the authors' work found that there is a histone-mimicry motif in SARS-CoV-2 of the new coronavirus, which disrupts the immune response
to viral infection by disrupting the chromatin regulation of host cells during viral infection.
ORF8 is associated with chromatin and disrupts the regulation of post-translational modifications of key histones and promotes chromatin coagulation (Figure 3).

Deletion of the histone-mimetic motif in ORF8 or it impaires the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection, and attenuates viral genome copy number
.
This work has important implications
for understanding the pathogenesis of COVID-19 in patients with deletions and mutations in the ORF8 gene.

A opinion piece in the same journal reviews the work titled SARS-CoV-2 mimics a host protein to bypass defences, where the SARS-CoV-2 virus has evolved to mimic one of the DNA-encapsulating histones in the nucleus, and this mimicry leads to disruption of gene transcription and weakening of the antiviral response
。