Summary auto-generated
This study examined how human papillomavirus (HPV) E6 proteins interact with Bak, a pro-apoptotic protein involved in cell death regulation. HPV must replicate in terminally differentiating epithelial cells where DNA replication normally triggers apoptosis. The E6 protein prevents this by degrading p53, but researchers found it also targets Bak. Using in vitro binding assays, cell-based degradation studies, and apoptosis assays, the authors demonstrated that E6 proteins from high-risk oncogenic HPV types (HPV-16 and HPV-18) and low-risk non-oncogenic HPV-11 all bind to and degrade Bak, reducing Bak-induced apoptosis. However, HPV-11 E6 was significantly less effective at all these functions than the oncogenic E6 proteins. The degradation process depends on E6-AP, a cellular ubiquitin ligase. These findings suggest that efficient suppression of Bak-mediated apoptosis may be important for viral oncogenic potential, since oncogenic HPVs replicate in upper epithelial layers where inappropriate DNA replication would trigger strong apoptotic responses.
Key findings
- E6 proteins from both high-risk (HPV-16, HPV-18) and low-risk (HPV-11) HPV types bind to and promote degradation of the pro-apoptotic protein Bak in vivo
- Oncogenic HPV E6 proteins are significantly more efficient at degrading Bak and blocking Bak-induced apoptosis compared to non-oncogenic HPV-11 E6
- The E6-mediated degradation of Bak is specific and depends on the cellular E6-AP ubiquitin ligase, the same protein required for p53 degradation
- The ability of E6 to abrogate Bak-induced apoptosis correlates directly with its efficiency in stimulating Bak degradation
- Differential Bak suppression between oncogenic and non-oncogenic HPVs may reflect their distinct replication sites in epithelium and contribute to viral oncogenic potential
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Abstract
Human papillomavirus (HPV) replication occurs in terminally differentiating epithelium, and requires the activation of cellular DNA replication proteins. Unscheduled DNA replication can result in the induction of apoptosis, and the viral E6 protein induces the degradation of p53 to prevent this. It has recently been shown that HPV-18 E6 can also stimulate the degradation of Bak, a pro-apoptotic member of the Bcl-2 family. This report shows that the E6 proteins from HPV-18, HPV-16 and HPV-11 can all bind to Bak in vitro, stimulate its degradation in vivo and reduce Bak-induced apoptosis. However, the non-oncogenic HPV-11 E6 is less effective than the oncogenic E6 proteins in each of these assays, indicating that the ability of HPV to circumvent the apoptosis induced by Bak may contribute to the oncogenic potential of the virus.