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Identification of Nucleolar Factors During HIV-1 Replication Through Rev Immunoprecipitation and Mass Spectrometry
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Molecular insight into how HIV-1 Vpr protein impairs cell growth through two genetically distinct pathways

Claire Maudet1, Matthieu Bertrand, Erwann Le Rouzic

  • 1Inserm, U1016, Institut Cochin, Paris 75014, France.

The Journal of Biological Chemistry
|May 14, 2011
PubMed

Insights

The HIV Vpr protein uses DCAF1 to target cellular proteins, causing cell cycle arrest and death. A specific motif (SRIG) is crucial for G2 arrest, while other functions of Vpr independently cause cell death.

Area of Science:

  • Virology
  • Molecular Biology
  • Cell Biology

Background:

  • The human immunodeficiency virus (HIV) accessory protein Vpr plays a key role in viral pathogenesis.
  • Vpr hijacks the host cell's CUL4 ubiquitin ligase complex via DCAF1 to target cellular proteins.
  • This interaction leads to G2 phase cell cycle arrest and contributes to cell death.

Purpose of the Study:

  • To identify the specific regions of Vpr responsible for binding to DCAF1 and its cellular target.
  • To investigate the role of the conserved SRIG motif in Vpr-mediated G2 arrest.
  • To determine if Vpr exhibits cytopathic effects independent of G2 cell cycle arrest.

Main Methods:

  • Analysis of Vpr protein domains and mutations to map DCAF1 and target binding sites.
  • Construction of Vpr protein chimeras to study determinant mapping.
  • Assessment of G2 arrest, cell viability, colony formation, and apoptosis induction in Vpr-mutant expressing cells.

Main Results:

  • The three alpha-helices of Vpr are essential and sufficient for DCAF1 binding.
  • Non-linear determinants within Vpr are required for cellular target binding.
  • A conserved SRIG motif is critical for Vpr-induced G2 arrest and may predict G2 arrest capacity in other SIV Vpr proteins.
  • Vpr mutants defective in G2 arrest but proficient for DCAF1 binding still exhibit cytopathic effects, including inhibition of colony formation and lymphocyte cytotoxicity, independent of G2 arrest.
  • These G2 arrest-defective mutants induce apoptosis via caspase 3.
  • Disrupting DCAF1 binding rescues colony formation, but DCAF1 binding alone does not confer cytopathicity.

Conclusions:

  • Vpr utilizes distinct determinants for DCAF1 and cellular target interaction.
  • The SRIG motif is a key determinant for Vpr-mediated G2 arrest.
  • Vpr possesses a DCAF1-dependent, G2 arrest-independent cytopathic mechanism involving apoptosis induction.
  • Vpr likely recruits DCAF1 to promote the degradation of host proteins essential for cell growth, contributing to viral pathogenesis.

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