Drawing on disorder: How viruses use histone mimicry to their advantage

Tarakhovsky, Alexander; Prinjha, Rab K.

The first example of viral histone mimicry was the identification of a histone H3-like sequence within the C-terminal portion of in G9a (red hexagon) binds to the chromodomain-containing protein HP1γ, which can also interact with methylated histone H3 (red hexagon). (B) The NS1 proteins of the influenza A H3N2 virus possess a functional histone H3K4-like sequence (yellow letters), localized within the nonstructured C terminus of the protein, whereas the homologous H3 sequence (red letters) is localized within its N terminus. The NS1 histone mimic (yellow tail) is present in the nucleus, where it interacts with Paf1 complex and Chd1 proteins. Interaction with Chd1 depends on NS1 lysine methylation, whereas Paf1 can bind to the unmethylated or methylated NS1 histone mimic. The pattern of Paf1 and Chd1 binding to NS1 is similar to the interactions between these proteins and histone H3. The schematic model describes a putative mechanism of NS1 interference with Paf1-mediated transcription of virus-induced genes. (C) Histone mimicry by the core protein of the YFV. The N-terminal portion (40 aa) of the H4 histone and the YFV core protein display a high degree of homology, and share the presence of the lysine residues in YFVC that become acetylated in the infected cells (not depicted). The intrinsic disorder of viral proteins that carry histone mimics (red) may facilitate multiple interprotein interactions followed by formation of phase-separated viral protein condensates (liquid droplets). The ability to form liquid droplets may maximize the impact of viral proteins, including those that carry histone mimics, on chromatin followed by alteration of host chromatin-associated the nonstructural protein 1 (NS1) of the H3N2 subtype of influenza A virus (Marazzi et al., 2012; Fig. 2 B) . The NS1 protein suppresses the type I IFN response during influenza infection (García-Sastre et al., 1998; Wang et al., 2000) and is essential for virus infection. The sequence 226-ARSK-229 of NS1 resembles the first four amino acids (1-ARTK-4) of the histone H3 protein.