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

Tarakhovsky, Alexander; Prinjha, Rab K.

Phase separation contributes to the formation of numerous intracellular membraneless organelles, including PML bodies and the nucleolus (Banani et al., 2017; Woodruff et al., 2018) . One of the potentially relevant aspects of viral histone mimicry relates to the compartmentalization of viral proteins to the nucleolus. The presence of viral proteins, including core proteins of different flaviviruses, leads to nucleolar stress followed by up-regulation of p53 and cell death (Rawlinson and Moseley, 2015; Slomnicki et al., 2017; Yan et al., 2017) . Virus-induced nucleolar stress and cell death cannot be beneficial for the virus, and is thus likely to represent a rather dramatic effort by the cell to limit spread of infection and effectively counteract viral histone mimicry. Moreover, phagocytosis of cells killed by viruses will amplify the systemic immune response against infection. It is tempting to speculate that nucleolar stress represents an innate defense pathway that involves host-mediated uptake of viral proteins to the nucleolus followed by their recognition by hypothetical host-encoded sensors and subsequent nucleolar stress. As such, it is possible that nucleolar proteins, such as TCOF1 or other proteins involved in prevention of the nucleolar stress (Calo et al., 2018) , bind to nonmodified or posttranslationally modified viral histone mimics, followed by alteration of nucleolar function and death of infected cells (Fig. 3 B) .