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Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

Claire Séror1, Syed Qasim Raza, Fanélie Brottes

  • 1INSERM, U848, Villejuif, France.

Cell Cycle (Georgetown, Tex.)
|January 30, 2009
PubMed

Insights

Checkpoint kinase 2 (Chk2) mediates apoptosis in HIV-1 Env-induced syncytia by participating in the DNA damage response. Chk2, but not Chk1, is crucial for initiating programmed cell death in these multinucleated giant cells.

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Fusogenic HIV-1 isolates cause infected and bystander cells to fuse, forming multinucleated giant cells (syncytia) observed in lymphoid tissues and the brain.
  • HIV-1 envelope glycoprotein (Env) induces syncytia formation, characterized by PML aggregation, recruitment of DNA damage response proteins (TopBP1, NBS1, ATM), and activation of apoptosis via p53.

Purpose of the Study:

  • To investigate the role of checkpoint kinases 1 and 2 (Chk1 and Chk2) in the DNA damage response and apoptosis of HIV-1 Env-induced syncytia.
  • To determine whether Chk1 or Chk2 is essential for the programmed cell death pathway in syncytia.

Main Methods:

  • Analyzing syncytia for activating phosphorylations of Chk1 and Chk2, and their colocalization with DNA damage foci (γ-H2AX).
  • Utilizing siRNA-mediated knockdown to assess the impact of Chk1 and Chk2 depletion on syncytial apoptosis.
  • Investigating the effect of depleting PML, TopBP1, NBS1, or ATM on Chk2 phosphorylation.

Main Results:

  • Env-induced syncytia exhibit activating phosphorylations of both Chk1 and Chk2, which colocalize with γ-H2AX foci.
  • Knockdown of Chk2, but not Chk1, significantly inhibits mitochondrial outer membrane permeabilization and subsequent apoptosis in syncytia.
  • Depletion of PML, TopBP1, NBS1, or ATM prevents the activating phosphorylation of Chk2.

Conclusions:

  • Chk2 plays a critical role in the DNA damage-induced pro-apoptotic cascade leading to the elimination of HIV-1 Env-elicited syncytia.
  • Chk1 is not essential for this apoptotic pathway, highlighting a specific role for Chk2 in HIV-1 syncytia-mediated cell death.

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