STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• Human papillomaviruses (HPV) rely on host factors for their life cycle.
• Signal transducer and activator of transcription (STAT)-3 regulates cell cycle and survival.
• STAT3 requires dual phosphorylation for transcriptional activity.

Purpose of the Study:

• To investigate the role of STAT3 in the HPV life cycle.
• To determine how HPV18 manipulates STAT3 activity.
• To assess the therapeutic potential of targeting STAT3 in HPV infections.

Main Methods:

• Analyzing STAT3 phosphorylation in HPV18-infected keratinocytes.
• Investigating the effect of HPV18 E6 oncoprotein on STAT3.
• Utilizing siRNA, small molecule inhibitors, and dominant-negative mutants to block STAT3.
• Employing organotypic raft cultures to model HPV infection and differentiation.
• Examining STAT3 expression in cervical disease biopsies.

Main Results:

• HPV18 infection enhances STAT3 phosphorylation in keratinocytes.
• HPV18 E6 protein induces dual STAT3 phosphorylation via JAK and MAPK pathways.
• Activated STAT3 upregulates cyclin D1 and Bcl-xL, promoting cell cycle progression.
• STAT3 inhibition or mutation blocks HPV replication, episome maintenance, and late gene expression.
• STAT3 activation is elevated in HPV-positive cervical biopsies, correlating with carcinogenesis.

Conclusions:

• STAT3 is essential for the HPV18 life cycle, from initial infection to viral replication and differentiation.
• HPV18 E6 exploits the STAT3 pathway to drive viral proliferation and potentially cervical cancer.
• Targeting STAT3 activation presents a potential therapeutic strategy against HPV infections.