Human cytomegalovirus infection induces L1 expression through UL38-dependent mTOR-KAP1 pathway

Human cytomegalovirus (HCMV) and LINE-1 (L1) can co-inhabit a common host and closely interact with each other within a single cell. We have previously shown that HCMV exploits this opportunistic interaction by upregulating L1 expression that promotes its own productive life cycle by facilitating HCMV DNA replication. However, the mechanism by which HCMV increases L1 expression remains unknown. Here, we report that HCMV infection functionally inactivates KRAB-associated protein 1 (KAP1), a key epigenetic repressor of L1, through phosphorylation. HCMV infection of cells activates mTOR kinase that phosphorylates S824 residue of KAP1 and reduces its epigenetic repressive function, leading to increased chromatin accessibility of L1 promoter region. Treatment of potent mTOR inhibitor to the HCMV-infected cells was sufficient to reduce KAP1 phosphorylation and block L1 expression. Furthermore, cells infected with a mutant virus lacking UL38, an HCMV mTOR pathway activator, showed reduced KAP1 S824 phosphorylation and abolished L1 expression. Our results highlight the synergistic interaction between HCMV and L1 where HCMV UL38 serves as a primary viral regulator of L1 expression by upregulating the mTOR-KAP1 pathway.