HPV E6 proteins target Ubc9, the SUMO conjugating enzyme.

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• Human papillomavirus (HPV) oncogenic E6 protein targets cellular proteins for degradation via the ubiquitin-proteasome pathway.
• SUMOylation, a post-translational modification, regulates protein activity, interactions, and stability.
• Ubc9 is the sole SUMOylation conjugation enzyme in host cells.

Purpose of the Study:

• To investigate the effect of high-risk HPV E6 proteins on Ubc9 levels and host cell sumoylation.
• To determine if HPV E6 targets Ubc9 for degradation and how this impacts sumoylation.
• To explore the role of Ubc9 modulation by HPV E6 in viral pathogenesis and cervical cancer.

Main Methods:

• Assessing Ubc9 intracellular quantity and transcription levels in the presence of HPV E6.
• In vitro binding assays between E6 and Ubc9.
• Evaluating the requirement of E6AP in E6-mediated Ubc9 reduction.
• Analyzing Ubc9 and sumoylated target levels in differentiating keratinocytes expressing E6.

Main Results:

• High-risk HPV E6 proteins significantly reduce intracellular Ubc9 levels.
• E6-mediated Ubc9 reduction occurs at the protein level, not via transcription changes.
• E6 binds to Ubc9 in vitro and requires E6AP for Ubc9 degradation.
• Stable E6 expression leads to decreased Ubc9 and loss of numerous sumoylated targets in keratinocytes.

Conclusions:

• HPV E6 targets the Ubc9 protein, the sole SUMOylation enzyme, to reduce host cell sumoylation.
• This disruption of the sumoylation system by E6 is likely important for viral replication.
• Modulation of Ubc9 by HPV E6 may contribute to the development of cervical cancer.