SARS-CoV-2 virus has evolved to mimic the structure of chromosomal histones in the cell nucleus. This camouflage ability leads to disruption of gene transcription in human cells and weakened antiviral responses.
In order to fight viral infection, human cells must make rapid and effective immune defense responses. Meanwhile, viruses have evolved cunning strategies to interfere with or bypass the host cell's defense mechanisms.
Recent studies have revealed a strategy of SARS-CoV-2 to escape the human cell defense system by mimicking the chromosomal histone structure of human cells. This camouflage destroys the host cell's ability to regulate gene expression and respond effectively to infection.
So far, histone simulations have been shown to be applicable to a small number of viruses, but this is the first time that conclusive evidence has been found for members of the coronavirus family using this immune defense evasion strategy.
Since the beginning of the COVID-19 pandemic, people have been studying why SARS-CoV-2 is so good at replicating in humans and how it causes disease. The genome of
virus encodes non-structural proteins, structural proteins and auxiliary proteins required for viral replication. Now researchers are particularly interested in the third group of protein .
Compared with other viral proteins, auxiliary proteins are less evolutionarily conservative. Helper proteins affect disease severity or the interaction of the virus with the host, or interfere with the host immune response, allowing the virus to replicate effectively within the host.
SARS-CoV-2 disrupts chromatin regulation by promoting the formation of densely packed "heterochromatin" regions, inhibits the expression of genes in chromatin , resulting in a decrease in antiviral response.
researchers investigate whether histone simulations that assist protein may play a role in this process.
They began with a bioinformatics investigation and compared the sequences of all SARS-CoV-2 proteins with those of all human histones.
They found that the tail region of SARS-CoV-2 helper protein Orf8 and human histone H3 share the sequence of six amino acid residues . These six are alanine , arginine , lysine , serine , alanine and proline (collectively referred to here as ARKSAP, using its standard single-letter abbreviation). The first four residues of
ARKSAP, known as the ARKS motif, were also discovered for the second time in the tail region of histone H3. The two ARKS motifs in
H3 are usually attached or removed from enzyme-modified sites of molecular groups such as acetyl or methyl (this phenomenon is called post-translational modification).
In addition, they are key regulatory regions: acetylation or methylation of lysine residues in the ARKS motif helps to activate or inhibit DNA expression in chromatin, respectively.
researchers speculate that the "similar" ARKS motif in Orf8 may allow viral proteins to act as histone mimics, thus interfering with H3 function.
To confirm this idea, the researchers introduced the gene encoding Orf8 into human cells.
They found that Orf8 protein can be detected in the nucleus (which is unusual for most coronavirus proteins). Orf8 protein interacts with H3-containing protein complexes involved in maintaining nuclear and chromatin structures in the nucleus.
In contrast, protein versions lacking the ARKS motif showed reduced binding to chromatin in the nucleus. The ARKS motif of
Orf8 is modified by acetylation, just like the motif of H3. The levels of KAT2A, the enzyme responsible for this post-translational modification, were significantly reduced after Orf8 was expressed in cells.
These data suggest that Orf8 can interfere with histone post-translational modifications, possibly by triggering the degradation of KAT2A, just like other proteins it binds to.
In addition, after Orf8 expression, histone modifications associated with active gene expression (H3 and other histones) were reduced, and modifications associated with chromatin compaction and transcriptional repression were increased.
Perhaps this is a result of reduced KAT2A levels, although other enzymes mediating histone modifications may also be directly or indirectly affected by Orf8.
Next, the researchers explored whether Orf8 had the same effect on chromatin and histone regulation in SARS-CoV-2-infected cells.
They designed mutant strains of SARS-CoV-2, which either lack the entire gene encoding Orf8, or express a protein version that lacks only the ARKSAP sequence.
, unlike wild-type viruses, both modified Orf8 mutant viruses lack the ability to destroy the chromatin of the host cell, suggesting that the ARKSAP sequence is responsible for this effect.
What about other virus characteristics?
researchers found that viral replication was only slightly affected by the deletion, but transcription in host cells was altered. The transcriptional responses of
-infected virus-infected cells and Orf8-deficient viruses have differential responses to infection, but they also differ between cells infected with Orf8-deficient viruses and viruses that lack only ARKSAP.
This suggests that other fields of Orf8 also have the function of eventually generating transcriptional changes in genes. Previous studies of
are consistent with this view, suggesting that Orf8 alters the activity of certain immune pathways.
reduces translocation of interferon regulators of immune proteins to the nucleus, promotes stress responses in organelles called endoplasmic reticulum and mediates the degradation of immune proteins called MHC proteins.
This study adds another layer to our understanding of how SARS-CoV-2 interacts with host cells.
is important to further study how Orf8 activity changes viral infection and transmission, as well as the development of human diseases.
The naturally occurring deletion in the SARS CoV-2 gene encoding Orf8, found in Singapore , in 2020, is associated with less severe disease and may provide the first hint.
It is not clear whether the severity of this variant is directly related to changes in histone simulations, but the association suggests that coronavirus helper proteins can play a role in disease severity.
This study raises questions about the evolution of viruses and adaptation to humans. Most proteins in
SARS-CoV-2 and related virus SARS-CoV (2003 "SARS" coronavirus) are highly evolutionarily conserved. In addition to Orf3b and Orf8, the Orf8 protein of SARS-CoV lacks the ARKS motif. In contrast, some of the coronaviruses associated with SARS in bats show this trait.
This may indicate that SARS-related coronaviruses are evolving to use helper proteins and histone simulations as part of their interference strategies.
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