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A Comparative Approach to Characterize the Landscape of Host-Pathogen Protein-Protein Interactions
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Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin-proteasome system

Juline Poirson1, Elise Biquand2, Marie-Laure Straub1

  • 1Ecole Supérieure de Biotechnologie Strasbourg, UMR-7242, CNRS, Université de Strasbourg, Illkirch, France.

The FEBS Journal
|August 9, 2017
PubMed

Insights

Researchers identified novel interactions between human papillomavirus (HPV) oncoproteins E6 and E7 and the ubiquitination system. This study reveals new viral strategies targeting host protein regulation for replication and immune evasion.

Area of Science:

  • Biochemistry and Molecular Biology
  • Virology
  • Cellular Biology

Background:

  • Protein ubiquitination and deubiquitination are crucial cellular processes regulating protein fate, catalyzed by ubiquitin ligases and deubiquitinases (DUBs).
  • The Ub-proteasome system (UPS) is frequently exploited by viruses, including human papillomavirus (HPV), to facilitate viral replication and evade host immune responses.
  • Understanding viral interactions with the UPS is key to deciphering viral pathogenesis and developing antiviral strategies.

Discussion:

  • This study screened a library of UPS-related cDNAs to identify novel partners of HPV16 E6 and E7 oncoproteins using a protein complementation assay.
  • HPV16 E6 was found to interact with E3 ubiquitin ligases (E6AP, MGRN1, LNX3, LNX4) and the DUB USP15, with specific binding preferences observed for LNX3 and LNX4 across different HPV types.
  • HPV16 E7 interacted with various UPS components, including Cullin 3-RING and Cullin 4-RING E3 ligase adaptors, RING-type E3 ligases involved in innate immunity, and DUBs (USP29, USP33), with binding mediated by its C-terminal region.

Key Insights:

  • HPV16 E6 interacts with multiple E3 ubiquitin ligases and a DUB, suggesting multifaceted regulation of host protein turnover.
  • HPV16 E7 engages with diverse UPS factors, including those critical for innate immunity, highlighting viral subversion of host defense mechanisms.
  • Specific interactions, like LNX3 with high-risk HPV E6 and LNX4 with HPV16 E6, offer insights into HPV type-specific viral strategies.
  • The C-terminal region of HPV16 E7 is critical for its interactions with UPS components, distinct from the LxCxE motif.

Outlook:

  • The identified interactions provide a foundation for further investigation into the functional consequences of HPV oncoprotein engagement with the UPS.
  • This work establishes a robust screening strategy for discovering host-pathogen interactions within the ubiquitination system.
  • Further research could explore therapeutic interventions targeting these newly identified viral-host protein interactions to combat HPV infections.
Keywords:
HPVinteractomicprotein complementation assayubiquitination

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