Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• TWEAK (TNF superfamily member) induces diverse cell death pathways.
• The specific TWEAK receptor mediating these pathways was unknown.
• Fibroblast growth factor-inducible 14 (Fn14) was identified as a TWEAK receptor, but its role in cell death was unclear due to its lack of a death domain.

Purpose of the Study:

• To investigate the role of Fn14 in mediating TWEAK-induced cell death pathways.
• To determine if Fn14 can transmit TWEAK-induced death signals.
• To elucidate the sole receptor responsible for TWEAK-mediated cell death.

Main Methods:

• Utilized Fn14 transfectants to study TWEAK-induced apoptosis and necrosis.
• Employed a pan-caspase inhibitor to analyze cell death mechanisms.
• Generated agonistic anti-Fn14 monoclonal antibodies (mAbs) to assess Fn14 expression and function.
• Used blocking anti-Fn14 mAbs to inhibit TWEAK-Fn14 interaction.

Main Results:

• TWEAK induced apoptotic cell death in Fn14 transfectants.
• Caspase inhibition sensitized cells to TWEAK-induced necrosis via reactive oxygen intermediates and cathepsin B.
• Fn14 is constitutively expressed on TWEAK-sensitive tumor cell lines and transmits death signals.
• Blocking TWEAK-Fn14 interaction abrogated TWEAK binding and TWEAK-induced cell death.

Conclusions:

• Fibroblast growth factor-inducible 14 (Fn14) is the sole receptor mediating TWEAK-induced cell death.
• Fn14 transmits signals for both TWEAK-induced apoptosis and necrosis.
• Understanding the TWEAK-Fn14 axis offers insights into targeted cell death induction therapies.