Depletion of intracellular zinc inhibits the ubiquitin ligase activity of viral regulatory protein ICP0 and restricts herpes simplex virus 1 replication in cell culture.

The viral ubiquitin ligase ICP0 stimulates the onset of HSV-1 lytic infection and productive reactivation of viral genomes from latency. In order to mediate these processes, it requires its C3HC4 RING finger domain, a tertiary structural fold that is coordinated by the binding of two zinc (Zn(2+)) atoms. Here we formally demonstrate that Zn(2+) binding and intracellular Zn(2+) levels are critical for ICP0's biochemical activity and that depletion of intracellular Zn(2+) severely attenuates HSV-1 replication.