SUMO-targeted ubiquitin ligase that plays an essential role in nuclear antiviral defense evasion triggered by dsDNA viruses (PubMed:32001251). Acts during the initial stages of lytic infection and the reactivation of latent viral genome. Prevents the antiviral effect of nuclear bodies by degrading host PML, SP100 and MORC3 (PubMed:27440897, PubMed:34759314). Prevents antiviral response to viral DNA induced by IFI16 by degrading it. Additionally, inhibits host IRF3 nuclear signaling to prevent interferon production by the infected cells. Interestingly, the E3 ubiquitin ligase activity associated with the RING finger domain does not seem to be directly required to inhibit the activation of IRF3 but instead plays a critical role in modulating the cellular localization of ICP0. Upon reactivation of latent genome, suppresses the silencing of viral DNA by dissociating either HDAC1 or HDAC2 from the HDAC-RCOR1-REST-KDM1A complex localized at the ND10 structures and causes their dispersal. Two cellular histone ubiquitin ligases RNF8 and RNF168 are also targeted by ICP0 for degradation, leading to a loss of ubiquitinated forms of H2A, a relief of transcriptional repression, and the activation of latent viral genomes. Enhances the localization of host CCND3 to ND10 bodies that serve as precursors of replication compartments to enable efficient viral replication. Like many RING-finger E3 ubiquitin ligases, ICP0 can induce its own ubiquitination, an activity that promotes its instability due to its targeting to the 26S proteasome for degradation. ICP0 restricts this process by recruiting the cellular ubiquitin-specific protease USP7 that cleaves the anchored ubiquitin chains from ICP0, thereby promoting its stabilization. S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. Interacts directly with human RCOR1/CoREST protein, leading to the disruption of the human BHC corepressor complex (PubMed:15897453). Interacts with human CENPA, leading to its degradation (PubMed:11053442). Interacts with human USP7; this interaction modulates ICP0 stability (PubMed:14506283, PubMed:18590780). Interacts with human CDC34 (PubMed:11447293). Interacts (when phosphorylated) with human RNF8 (via FHA domain) (PubMed:22405594). Interacts with human TRIM27 (PubMed:25320289). Interacts with human ZBP1 (PubMed:23283962). Interacts with host MORC3; this interaction promotes the degradation of host MORC3 (PubMed:27440897, PubMed:34759314). Phosphorylated at Thr-67, leading to promote interaction with host RNF8 (PubMed:22405594). Phosphorylated by host CHEK2; leading to increased SUMO-targeted ubiquitin ligase activity of ICP0 (PubMed:32001251). Auto-ubiquitinated. Deubiquitinated by host USP7; leading to stabilize it. Belongs to the simplexviruses ICp0 family.