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Inhibition of lymphotoxin-beta receptor-mediated cell death by survivin-DeltaEx3

Ren-In You1, Mei-Chieh Chen, Hsei-Wei Wang

  • 1Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.

Cancer Research
|March 17, 2006
PubMed

Insights

Survivin-DeltaEx3 protects cells from tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT)-induced cell death by regulating both caspase-dependent and independent pathways. This viral inhibitor of apoptosis protein maintains mitochondrial function, unlike KSHV-K7.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Virology

Background:

  • TNFSF14/LIGHT binding to LTbetaR triggers cell death via caspase-dependent and -independent routes.
  • Cellular inhibitor of apoptosis proteins (IAPs) can impede LTbetaR-mediated cell death.
  • Kaposi's sarcoma-associated herpesvirus K7 (KSHV-K7) is a viral IAP.

Purpose of the Study:

  • To investigate the differential effects of KSHV-K7 and survivin-DeltaEx3 on LTbetaR-mediated cell death pathways.
  • To elucidate the mechanisms underlying survivin-DeltaEx3's protective role against LTbetaR signaling.

Main Methods:

  • Assessed inhibition of caspase-3 activation by KSHV-K7 and survivin-DeltaEx3.
  • Evaluated cell viability and mitochondrial membrane potential.
  • Measured second mitochondria-derived activator of caspase/DIABLO release and reactive oxygen species production.
  • Tracked survivin-DeltaEx3 translocation and its interaction with apoptosis signal-regulating kinase 1 (ASK1).

Main Results:

  • Both KSHV-K7 and survivin-DeltaEx3 inhibited LTbetaR-induced caspase-3 activation.
  • Only survivin-DeltaEx3 conferred protection against LTbetaR-mediated cell death.
  • Survivin-DeltaEx3 preserved mitochondrial membrane potential, inhibited DIABLO release, and reduced reactive oxygen species.
  • Survivin-DeltaEx3 translocated to the cytosol and associated with ASK1 following LTbetaR activation.
  • Survivin-DeltaEx3 protected LTbetaR-mediated cell death even in caspase-3-deficient cells.

Conclusions:

  • Survivin-DeltaEx3 regulates both caspase-dependent and -independent cell death pathways induced by LTbetaR.
  • Inhibition of the caspase-independent pathway by survivin-DeltaEx3 is crucial and sufficient for its protective effect.
  • Survivin-DeltaEx3's ability to maintain mitochondrial integrity underlies its potent anti-apoptotic function.

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