Abstract
Dysregulation of the constitutive heterochromatin machinery (HCM) that silences pericentromeric regions and endogenous retroviral elements in the human genome has consequences for aging and cancer. By recruiting epigenetic regulators, Krüppel-associated box (KRAB)-associated protein 1 (KAP1/TRIM28/TIF1β) is integral to the function of the HCM. Epigenetically silencing DNA genomes of incoming herpesviruses to enforce latency, KAP1 and HCM also serve in an antiviral capacity. In addition to gene silencing, newer reports highlight KAP1's ability to directly activate cellular gene transcription. Here, we discuss the many facets of KAP1, including recent findings that unexpectedly connect KAP1 to the inflammasome, reveal KAP1 cleavage as a novel mode of regulation, and argue for a pro-herpesviral KAP1 function that ensures transition from transcription to replication of the herpesvirus genome.