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The high-risk HPV E6 oncoprotein preferentially targets phosphorylated nuclear forms of hDlg
Nisha Narayan1, Vanitha Krishna Subbaiah, Lawrence Banks
1Tumour Virology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, Trieste, TS 34012, Italy.
Abstract:
High-risk mucosal HPV E6 oncoproteins target a number of PDZ domain-containing substrates for proteasome mediated degradation. One of these, Discs Large (Dlg), is involved in the regulation of cell polarity and proliferation control. Previous studies had suggested that Dlg when hyperphosphorylated by osmotic shock, or when present in the nucleus could be preferentially targeted by E6. In this study we use phospho-specific antibodies directed against Dlg phosphorylated at residues S158 and S442 to show that these two observations are, in fact, linked. Dlg, when phosphorylated on S158 and S442 by CDK1 or CDK2, shows a preferential nuclear accumulation. However, these forms of Dlg are absent in cells derived from HPV-induced cervical cancers. Upon either proteasome inhibition or siRNA ablation of E6 expression, we see specific rescue of these phosphorylated forms of Dlg. These results demonstrate that nuclear forms of Dlg phosphorylated on its CDK phospho-acceptor sites has enhanced susceptibility to E6-induced degradation and place previous studies on the stress-induced phosphorylation of Dlg into a relevant biological context.
Insights
High-risk HPV E6 oncoproteins degrade Discs Large (Dlg) proteins. Phosphorylation of Dlg by CDK1/2 promotes nuclear accumulation and E6 targeting, linking stress responses to cancer progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Virology
Background:
- High-risk mucosal HPV E6 oncoproteins target PDZ domain-containing substrates for degradation.
- Discs Large (Dlg) protein regulates cell polarity and proliferation and is a target of HPV E6.
- Previous studies suggested Dlg is targeted by E6 when hyperphosphorylated or nuclear.
Purpose of the Study:
- To investigate the link between Dlg phosphorylation and nuclear accumulation in HPV E6-mediated degradation.
- To determine if specific phosphorylation sites on Dlg influence its susceptibility to E6 degradation.
- To contextualize stress-induced Dlg phosphorylation within HPV-induced cervical cancers.
Main Methods:
- Utilized phospho-specific antibodies against Dlg phosphorylated at S158 and S442.
- Employed CDK1 and CDK2 in phosphorylation studies.
- Observed Dlg forms in HPV-induced cervical cancer cells, with and without proteasome inhibition or E6 siRNA.
Main Results:
- Dlg phosphorylation at S158 and S442 by CDK1/2 leads to preferential nuclear accumulation.
- These phosphorylated nuclear Dlg forms are absent in HPV-induced cervical cancer cells.
- Proteasome inhibition or E6 siRNA rescues the presence of phosphorylated Dlg.
Conclusions:
- Nuclear Dlg phosphorylated on CDK sites exhibits increased susceptibility to E6-induced degradation.
- This finding links Dlg phosphorylation, nuclear localization, and HPV E6 activity.
- Places stress-induced Dlg phosphorylation into the biological context of cervical cancer development.
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