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Use of Interferon-γ Enzyme-linked Immunospot Assay to Characterize Novel T-cell Epitopes of Human Papillomavirus
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Mutational analysis of the discs large tumour suppressor identifies domains responsible for human papillomavirus type

Daniela Gardiol1, Silvina Galizzi1, Lawrence Banks2

  • 1Instituto de Biologia Molecular y Celular de Rosario (IBR-CONICET), Departamento de Microbiologia, Facultad de Ciencias Bioquimicas, Suipacha 531, 2000 Rosario, Argentina1.

The Journal of General Virology
|January 25, 2002
PubMed

Insights

High-risk human papillomavirus E6 proteins degrade the discs large (Dlg) tumor suppressor. This study reveals that while PDZ domain 2 is crucial for E6-mediated Dlg degradation, other Dlg regions also influence this process.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Discs large (Dlg) is a tumor suppressor protein.
  • High-risk human papillomavirus (HPV) E6 proteins target Dlg for degradation.
  • The precise mechanisms of Dlg regulation by E6 and intrinsic cellular pathways are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which HPV E6 proteins bind and degrade the Dlg tumor suppressor.
  • To identify specific domains and residues within Dlg critical for E6-mediated degradation.
  • To compare E6-dependent Dlg regulation with intrinsic proteasomal degradation pathways.

Main Methods:

  • Mutational analysis of the Dlg protein to assess the role of specific domains and residues.
  • Generation and analysis of stable cell lines expressing various Dlg mutants.
  • Assessment of Dlg protein stability and degradation in the presence and absence of HPV E6.

Main Results:

  • An intact PDZ domain 2 (PDZ2) of Dlg is essential for E6 binding and subsequent degradation.
  • Additional amino-terminal residues of Dlg are required for optimal E6-induced degradation.
  • Dlg is intrinsically regulated by the proteasome, with PDZ2 playing a significant role in this process.
  • The mechanisms regulating Dlg stability differ between E6-mediated and intrinsic proteasomal degradation.

Conclusions:

  • HPV E6 utilizes specific Dlg domains, notably PDZ2, for targeted degradation.
  • Dlg protein stability is controlled by at least two distinct regulatory mechanisms.
  • The cellular pathways governing Dlg stability in the absence of E6 are not identical to those employed by E6.

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