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

Tarakhovsky, Alexander; Prinjha, Rab K.

The other fascinating aspect of the histone mimicry-in the context of the overall disordered nature of NS1 and flavivirus core proteins-is the ability of IDP/IDR to facilitate formation of nonmembranous structures that are based on phase separation (Banani et al., 2017) . The multivalent protein-protein interactions often mediated by IDR can promote liquid-liquid separation to form membraneless cytoplasmic and nuclear compartments (Pontius, 1993; Oldfield et al., 2005; Weber and Brangwynne, 2012) . It has been speculated that assembly of numerous transcriptional regulators of the enhancer arrays (coined superenhancers [SE]) leads to formation of these gel-like structures complexes. The high concentration of the histone mimic within the phase-separated condensate may allow viral proteins to compete with cognate host chromatin proteins. The outcome of the competition may differ from loss of the host function, i.e., antiviral gene expression, or generation of aberrant virus-host hybrid protein complexes and acquisition of a new cell phenotype that can benefit viral replication. (B) Upon infection, viral RNA (vRNA) recognition by sensor proteins (e.g., RIG-I, MDA5) leads to activation of IFN and IFN-driven antiviral immunity. As infections progress, vRNA transcription and translation yield viral proteins, including those that carry histone mimics. The accumulation of viral histone mimics in the nucleolus of the infected cells might be sensed by dedicated (as yet unknown) sensors followed by nucleolar stress and death of the infected cell, thereby limiting the spread of viral infection. (Hnisz et al., 2017) . In their model, Hnisz et al. (2017) postulate that multiple components of SEs, including bromodomain-containing transcriptional regulator BRD4, RNA Pol II, and RNA, can form cross-links, defined as "any reversible feature, including reversible chemical modification, or any other feature involved in dynamic binding and unbinding interactions" (Hnisz et al., 2017) . Given the documented or computationally predicted abundance of IDRs in many of the transcriptional regulators, the cross-link is likely to reflect the multivalency of the IDP or IDR. The liquid phase separation at the SEs is likely to increase the fragility of these transcriptional hubs to perturbations based on the interaction between virus-derived and host-derived gel-like compartments rather than on specific protein-protein interactions. In this scenario, the viral IDP will interact with chromatin not as an individual protein but rather as a virus-derived protein-based membranous organelle (Fig. 3 A) . Such interaction is likely to have a dramatic impact on chromatin function, as it will drastically increase the concentration of histone-like sequences in the vicinity of gene regulatory regions, followed by negative or positive changes in gene expression, including genes that are critical for the antiviral response as well as genes that support virus replication.