Viral-encoded enzymes that target host chromatin functions

Abstract

Ever since their existence, there has been an everlasting arms race between viruses and their host cells. Host cells have developed numerous strategies to silence viral gene expression whereas viruses always find their ways to overcome these obstacles. Recent studies show that viruses have also evolved to take full advantage of existing cellular chromatin components to activate or repress its own genes when needed. While in most cases viruses encode certain proteins to recruit or inhibit cellular factors through physical interactions, growing examples show that viral-encoded enzymes affect host chromatin structure through post-translationally modifying histones or other cellular proteins important for chromatin function. The most well-studied example is vSET encoded by paramecium bursaria chlorella virus 1. vSET specifically methylates histone H3 at lysine 27, causing genome-wide silencing of Polycomb target genes upon infection, thus mimicking the function of Polycomb repressive complex 2 (PRC2) in eukaryotes. Other examples include BGLF4 from Epstein-Barr virus that affects both condensin and topoisomerase II activity and Us3 from Herpes Simplex virus 1 that inhibits HDAC1 function through phosphorylation.

Fig. 1

vSET mimicks the function of Polycomb repressive complexes (PRCs) for gene transcriptional silencing. vSET or Ezh2 of PRC2 methylates histone H3 at K27 to create binding sites for the chromodomain of CBX protein of PRC1, which ultimately results in heterochromatin formation and gene silencing. The process can be reversed by the action of lysine demethylases (KDM) and acetyltransferases (KAT) converting H3K27me3, a gene repression state, to lysine-acetylated H3 (H3Kac), which recruits the bromodomain-containing proteins of chromatin remodeling complexes and transcriptional proteins, leading to euchromatin formation and transcription activation.

Fig. 2

Comparison of three-dimensional structures of vSET and mammalian SET7/9 lysine methyltransferases. (A) Solution structure of vSET bound to cofactor SAH and histone H3 peptide containing mono-methylated lysine 27. The two protomers of the C₂-symmetric dimer are shown in cyan and green. Domain I and domain II of one protomer are depicted in regular and pale cyan, respectively. The histone peptides are shown in gold, and SAH molecules in red. The N- and C-termini of the cyan protomer are labeled. (B) Crystal structure of SET7/9 in complex with p53 peptide and SAH. The preSET, SET and postSET domains are colored blue, cyan and orange, respectively. The peptide and cofactor are shown in the same colors as those in A.

Fig. 3

Viral encoded enzymes that interfere host chromatin functions. Examples of viral enzymes are shown that affect diverse range of infected host chromatin structure and function, ranging from covalent modifications of histone tails (Group 1), phosphorylation of HDAC (Group 2), to alteration of the activity of Topoisomerase II and condensin (Group 3).