HSV-1 temporally orchestrates RAP80 ubiquitination to balance viral replication and evasion [Hi-C]

Here, we showed that HSV-1 employs a biphasic strategy to dynamically regulate the host protein RAP80 through stage-specific ubiquitination, thereby coordinating its replication cycle. Upon entry, RAP80 undergoes phase separation to form antiviral condensates that encapsulate the viral genome and suppress viral transcription.

The HSV-1-encoded E3 ubiquitin ligase ICP0 counteracts this antiviral mechanism by mediating RAP80 ubiquitination to dissolve these condensates, facilitating viral replication. In middle stage, RAP80 depletion leads to accumulation of R-loops and activation of the cGAS–STING–apoptosis axis, threatening viral persistence. In response, in middle and late stage, the viral deubiquitinase UL36USP deubiquitinates and stabilizes RAP80 to suppress R-loop accumulation and this immune-triggered apoptosis.