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

Area of Science:

• Virology
• Epigenetics
• Molecular Biology

Background:

• Human cytomegalovirus (HCMV) and LINE-1 (L1) retrotransposons coexist within host cells.
• HCMV upregulates L1 expression to enhance its own DNA replication and life cycle.
• The mechanism of HCMV-mediated L1 upregulation was previously unknown.

Purpose of the Study:

• To elucidate the molecular mechanism by which HCMV increases L1 expression.
• To investigate the role of KRAB-associated protein 1 (KAP1) in HCMV-induced L1 upregulation.
• To identify viral factors regulating the mTOR-KAP1 pathway during HCMV infection.

Main Methods:

• Cell culture and HCMV infection models.
• Western blotting to detect KAP1 phosphorylation.
• Chromatin accessibility assays to assess L1 promoter activity.
• Treatment with mTOR inhibitors and analysis of HCMV mutants (UL38).

Main Results:

• HCMV infection phosphorylates KAP1 at S824, reducing its repressive function.
• This phosphorylation increases chromatin accessibility at the L1 promoter.
• mTOR kinase activation by HCMV drives KAP1 phosphorylation and L1 expression.
• HCMV UL38 protein is essential for activating the mTOR-KAP1 pathway and L1 upregulation.

Conclusions:

• HCMV infection functionally inactivates the epigenetic repressor KAP1 through mTOR-mediated phosphorylation.
• The HCMV UL38 protein acts as a key viral regulator, activating the mTOR-KAP1 pathway to upregulate L1 expression.
• This synergistic interaction between HCMV and L1 is crucial for viral replication.