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Inhibition of Bak-induced apoptosis by HPV-18 E6
Abstract:
Human papillomavirus (HPV) E6 proteins inhibit apoptosis in both p53-dependent and p53-independent manners. A key point in apoptosis is the regulation provided by the Bcl-2 family; and in differentiating keratinocytes, in which HPV replicates, the Bak protein is highly expressed. We show that HPV-18 E6 will inhibit Bak-induced apoptosis and this is mediated by an interaction between the E6 and Bak proteins resulting in degradation of the Bak protein in vivo. We also show that Bak protein interacts with the ubiquitin ligase, E6AP, and that a mutant of Bak defective in E6AP binding is overexpressed in comparison with wild type. These studies suggest that Bak is probably the first naturally occurring target of E6AP to be identified.
Insights
Human papillomavirus (HPV) E6 protein targets Bak protein for degradation, inhibiting apoptosis. This interaction reveals Bak as a novel E6AP target, impacting cellular processes.
Area of Science:
- Molecular Biology
- Virology
- Cellular Biology
Background:
- Human papillomavirus (HPV) E6 proteins are known to inhibit apoptosis through p53-dependent and independent pathways.
- The Bcl-2 family regulates apoptosis, with Bak protein highly expressed in differentiating keratinocytes where HPV replicates.
Purpose of the Study:
- To investigate the mechanism by which HPV-18 E6 inhibits Bak-induced apoptosis.
- To identify the interaction between HPV-18 E6 and Bak proteins.
- To determine if Bak is a natural substrate for the ubiquitin ligase E6AP.
Main Methods:
- Investigated the interaction between HPV-18 E6 and Bak proteins.
- Assessed the degradation of Bak protein in vivo.
- Examined the interaction of Bak protein with the ubiquitin ligase E6AP using wild-type and mutant Bak.
Main Results:
- HPV-18 E6 inhibits Bak-induced apoptosis via a direct interaction with Bak.
- This interaction leads to the in vivo degradation of Bak protein.
- Bak protein interacts with E6AP, and a Bak mutant defective in E6AP binding shows increased expression compared to wild type.
Conclusions:
- HPV-18 E6 targets and degrades Bak protein, thereby inhibiting apoptosis.
- Bak is identified as a natural substrate for the ubiquitin ligase E6AP.
- These findings elucidate a novel mechanism of viral oncoprotein-mediated apoptosis evasion.