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When the Herpes Simplex virus (HSV) genome enters the nucleus for replication and transcription, phase-segregated nuclear protein bodies called PML Nuclear Bodies (PML NBs) colocalize with the genome and repress it. HSV encodes a SUMO-targeted Ubiquitin ligase ICP0 that degrades PML NBs to alleviate the repression. The molecular mechanism used by ICP0 to target PML NBs is unclear. For reasons unknown, the growth of HSV is dependent on the ATM/Chk2 pathway. Here we identify a bonafide SUMO-Interacting motif in ICP0 (SLS4) that is essential and sufficient to target SUMOylated proteins in PML NBs like PML and Sp100. Phosphorylation of SLS4 creates new salt-bridges between SUMO and SLS4, increases the SUMO/SLS4 affinity and switches ICP0 into a potent STUbL. We also report that ICP0 exploits the kinase Chk2 to phosphorylate SLS4 and enhance its STUbL activity. Our results uncover how a viral STUbL counters antiviral response by exploiting an unprecedented mechanism involving three post-translational modifications; ubiquitination, SUMOylation, and phosphorylation.

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