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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
08:47

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways

T Kataoka1, R C Budd, N Holler

  • 1Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Epalinges, CH-1066, Switzerland.

Current Biology : CB
|June 6, 2000
PubMed
Abstract

Insights

FLIP protein switches Fas signals from apoptosis to proliferation by activating NF-kappaB and Erk pathways, crucial for T cell interleukin-2 production.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • Fas receptor (CD95) activation by Fas ligand (FasL) typically induces apoptosis via caspase-8 and FADD.
  • However, Fas signaling can also promote cell proliferation, indicating a divergence in signaling pathways.
  • The proteins mediating this switch between apoptosis and proliferation remain incompletely understood.

Purpose of the Study:

  • To investigate the divergence point of conflicting Fas signals.
  • To identify the specific protein(s) responsible for switching Fas-mediated responses.

Main Methods:

  • Studied CD3-activated human T lymphocytes treated with recombinant FasL.
  • Analyzed the activation of transcription factors (NF-kappaB, AP-1) and signaling proteins (FLIP, RIP, Raf-1).
  • Assessed the role of FLIP in NF-kappaB and extracellular signal-regulated kinase (Erk) pathway activation and interleukin-2 production.

Main Results:

  • Recombinant FasL enhanced T cell proliferation and activated NF-kappaB and AP-1.
  • FLIP (FLICE-like inhibitory protein) was recruited and interacted with TNF-receptor associated factors, RIP, and Raf-1.
  • FLIP recruitment led to NF-kappaB and Erk pathway activation, critical for interleukin-2 production; increased FLIP expression enhanced IL-2 production.

Conclusions:

  • FLIP is not solely an inhibitor of Fas-induced apoptosis.
  • FLIP actively mediates the activation of NF-kappaB and Erk signaling pathways.
  • FLIP's capacity to recruit adaptor proteins is key to its dual role in Fas signaling.

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