Focal Adhesion Kinase Binds to the HPV E2 Protein to Regulate Initial Replication after Infection

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• Human papillomaviruses (HPV) are small DNA tumor viruses with lifecycles tied to epithelial differentiation.
• The mechanisms controlling HPV genome replication during initial infection remain largely unknown.
• The viral E2 protein is a key regulator of HPV DNA replication.

Purpose of the Study:

• To investigate the role of focal adhesion kinase (FAK) in regulating HPV replication.
• To determine if FAK interacts with and modifies the HPV E2 protein.

Main Methods:

• Utilized a specific PROTAC to deplete FAK in keratinocytes.
• Assessed HPV DNA content in keratinocytes with existing HPV-16/31 episomes and in those infected with HPV-16 quasiviruses.
• Studied the interaction and phosphorylation of the HPV E2 protein by FAK.

Main Results:

• FAK binds to and phosphorylates the high-risk HPV E2 protein.
• FAK depletion did not affect viral DNA content in cells already maintaining HPV-16 and HPV-31 episomes.
• FAK depletion significantly increased HPV-16 DNA content in cells infected with HPV-16 quasiviruses.

Conclusions:

• FAK plays a critical role in preventing HPV genome over-replication following initial infection.
• FAK's interaction with and phosphorylation of the E2 protein are key to controlling HPV DNA copy number.
• These findings elucidate a novel host-pathogen interaction mechanism in HPV infection.