A histone-like motif in yellow fever virus contributes to viral replication

The mimicry of host proteins by viruses contributes to their ability to suppress antiviral immunity and hijack host biosynthetic machinery 1 . Host adaptation to evade this exploitation depends on host protein functional redundancy 2 . Non-redundant, essential host proteins have limited potential to adapt without severe consequences 3 . Histones, which are essential for genome architecture and control of gene expression, are among the most evolutionary conserved proteins 4 . Here we show that the capsid protein of the flavivirus yellow fever virus (YFV), mimics histone H4 and interferes with chromatin gene regulation by BRD4, a bromodomain and extraterminal domain (BET) protein. Two acetyl-lysine residues of YFV capsid are embedded in a histone-like motif that interacts with the BRD4 bromodomain, affecting gene expression and influencing YFV replication. These findings reveal histone mimicry as a strategy employed by an RNA virus that replicates in the cytosol 5 and define convergent and distinct molecular determinants for motif recognition of the viral mimic versus histone H4.