Chimaeric HPV E6 proteins allow dissection of the proteolytic pathways regulating different E6 cellular target proteins

Oncogene. 2002 Nov 21;21(53):8140-8. doi: 10.1038/sj.onc.1206026.

Abstract

The ability of HPV E6 oncoproteins to induce the degradation of PDZ domain-containing MAGUK proteins correlates with their malignant potential. We previously showed that the HPV-6 E6 protein, when provided with the PDZ-binding domain from HPV-18 E6, acquires the ability to bind the Discs Large (Dlg) tumour suppressor and target it for degradation. Based on this finding we have extended this analysis to E6 proteins from a variety of different papillomavirus types. Cloning a PDZ-binding sequence onto the C-terminus of E6 proteins derived from low-risk mucosal, and low and high-risk cutaneous papillomavirus types, enables them to bind Dlg and a second MAGUK family member, MAGI-1. This renders the mucosally-derived low-risk chimaeric HPV E6 proteins capable of targeting Dlg for degradation, but they are unable to induce significant levels of degradation of MAGI-1. In contrast, none of the E6 proteins derived from cutaneous papillomavirus types induce significant degradation of either MAGI-1 or Dlg when provided with a PDZ-binding domain. These results demonstrate significant differences, both between mucosal and cutaneous HPV E6 proteins and in the pathways required for Dlg and MAGI-1 degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Consensus Sequence
  • DNA-Binding Proteins*
  • Discs Large Homolog 1 Protein
  • Genes, Synthetic
  • Guanylate Kinases
  • Humans
  • Membrane Proteins
  • Molecular Sequence Data
  • Nucleoside-Phosphate Kinase / metabolism*
  • Oncogene Proteins, Viral / chemistry
  • Oncogene Proteins, Viral / genetics*
  • Oncogene Proteins, Viral / metabolism*
  • Papillomaviridae / genetics
  • Papillomaviridae / pathogenicity
  • Protein Structure, Tertiary
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship

Substances

  • Adaptor Proteins, Signal Transducing
  • DLG1 protein, human
  • DNA-Binding Proteins
  • Discs Large Homolog 1 Protein
  • E6 protein, Cottontail rabbit papillomavirus
  • E6 protein, Human papillomavirus type 11
  • E6 protein, Human papillomavirus type 18
  • E6 protein, Human papillomavirus type 6
  • E6 protein, Human papillomavirus type 8
  • E6 protein, human papillomavirus type 1
  • Membrane Proteins
  • Oncogene Proteins, Viral
  • Proteins
  • Recombinant Fusion Proteins
  • protein E6, Bovine papillomavirus
  • Nucleoside-Phosphate Kinase
  • Guanylate Kinases