How do Viruses Regulate Host Cell Chromatin?
The mutual struggle between virus and host is expressed in terms of virus invasion and host defense. Chromatin is one of the barriers for host cells to resist viruses. The highly condensed chromatin structure destroys the accessibility of DNA, thereby resisting virus invasion. Viruses counter host cell defenses by manipulating host cell organelles, including dynamic changes in chromatin. Under normal conditions, host cells alter chromatin dynamics through regulatory factors such as DNA methylation, histone modifications, histone variants, chromatin remodeling, and non-coding RNAs. Interestingly, some viral proteins can mimic the molecular structure of these regulators, affecting host chromatin dynamics and subverting host cell defenses. This strategy, called molecular mimicry, is based on structural similarities between host and viral proteins and is widely used by viruses to regulate chromatin dynamics.
Molecular Mimicry of Viruses
Molecular mimicry affects epigenetic processes in host cells by interfering with heterochromatin formation, transcriptional silencing, DNA replication, and post-translational modification.
1. Mimic histone modification sequences
Viruses have a long tradition of mimicking histone sequences. Some viruses use the host's histones to package their genomes, while others use their own histones for genome packaging. Viral-encoded histones are distinct from host histones but can form similar nucleosome structures.
2. Mimic arginine finger
Arginine refers to a short sequence consisting of several consecutive arginines, which can selectively bind to acidic plaques (H2A-H2B acidic residues) formed on the surface of nucleosomes. The binding of non-histone proteins to acidic plaques of nucleosomes via arginine fingers is a common chromatin anchoring mechanism in cells. The arginine finger mimicked by the viral protein can effectively bind to the acidic plaques of the nucleosome and attach the virus to the chromatin.
3. Mimic linker histones
Adenovirus (Ad) protein pVII is a kind of protein-rich in basic amino acids, which mimics linker histone H1 and combines with viral DNA to form a "beaded structure" similar to nucleosomes. In addition to binding to viral DNA, pVII can also bind to host nucleosomes at the linker DNA, thereby inhibiting the accumulation of H2AX on the host genome and the DNA damage response. Attachment to chromatin not only ensures that different viruses can be bound, but also alters higher-order chromatin structural dynamics.
4. Mimic histone chaperone
The interaction between arginine fingers and acidic plaques occurs mainly in intact nucleosomes. Studies of the Epstein-Barr virus (EBV) protein BKRF4 have shown that BKRF4 tends to interact with partially unfolded nucleosomes at DNA breaks and interferes with the recruitment of RNF168, thereby preventing DDR signal propagation. The way BKRF4 binds to H2A-H2B or H3-H4 exhibits its histone chaperone function, suggesting that BKRF4 employs a histone chaperone mimic mechanism to interfere with nucleosome assembly and downstream protein recruitment.
5. Mimic DNA
White spot syndrome virus protein ICP11 is a protein-rich in acidic amino acids, which simulates the interaction between DNA and basic histones. ICP11 interacts with histones H2A, H2B, H3, and H2A.X. ICP11 may interfere with nucleosome assembly, preventing H2A.X from completing its key function of repairing DNA double-strand breaks. By occupying DNA-binding sites on histones, it regulates its DNA-binding activity, thereby affecting chromatin dynamics.
6. Mimic transcription factor
Studies have shown that Epstein-Barr virus protein EBNA2, as a transcription factor of viral proteins, can reorganize chromatin topology through phase separation and recruit histone acetyltransferase p300 to acetylate histone H3K27 in specific regions. Sequence similarities between EBNA2 and transcription factors suggest that virus-mimicking transcription factors mediate phase separation, which in turn affects chromatin dynamics.
References
- Yang Y.; et al. Phase separation of Epstein-Barr virus EBNA2 protein reorganizes chromatin topology for epigenetic regulation. Commun Biol. 2021, 4(1): 967.
- Liu Y.; et al. Virus-encoded histone doublets are essential and form nucleosome-like structures. Cell. 2021, 184(16): 4237-4250.e19
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