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

Tarakhovsky, Alexander; Prinjha, Rab K.

In conclusion, the histone mimicry by pathogens should be seen in a big picture context, whereby utilization of intrinsic disorder by viruses enables flexible, yet impactful, interaction with the host. The presence of histone mimics in structurally distinct viral proteins underscores the ability of viruses to use highly evolvable host protein sequences to develop optimal strategies for pathogen-host interaction. By imitating histones, viruses can challenge the adaptive capacity of the host cell, which cannot modify the primary sequence of histones without endangering the very foundation of its own cellular organization. In this scenario, the pressure imposed by viral proteins may have driven cells to devise a strategy whereby compartmentalization of viral proteins to the nucleolus leads to nucleolar stress and cell death. This could be seen as an example of a cell defense mechanism that minimizes the impact of viral disordered proteins on the host while preventing further viral spread. Finally, it is tempting to speculate that pharmacological imitation of the viral strategy to target multiple cellular components or single components that target multiple genes/proteins might yield therapeutic outcomes by altering attractors associated with pathological cell states including cancer or chronic inflammation.