Fig 8.

Working model. orf36 targets HDAC1 and 2 to facilitate MHV68 replication. At the core RTA promoter, orf36, in an enzymatic activity-dependent manner, induces phosphorylation of H2AX. At the distal promoter, orf36 inhibits HDAC1 and -2 association with this RTA promoter independent of the viral kinase enzymatic activity. However, orf36 enzymatic activity is likely necessary to also target as-yet-unidentified HDAC in order to enhance RTA promoter activity. In addition to directly regulating RTA promoters, orf36 counteracts HDAC1 and -2 to promote viral DNA synthesis and MHV68 replication in primary macrophages.