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TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation
Tatsuya Saitoh1, Masafumi Nakayama, Hiroyasu Nakano
1Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. shojmmb@tmd.ac.jp
The Journal of Biological Chemistry
|July 4, 2003
Summary
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) activates NF-kappaB signaling through fibroblast growth factor-inducible 14. TWEAK uniquely induces prolonged NF-kappaB activation via both canonical and non-canonical pathways, involving TRAF proteins.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a TNF superfamily member known to influence angiogenesis, apoptosis, and NF-kappaB activation.
- TWEAK exerts its effects by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14).
- NF-kappaB signaling plays a critical role in immune responses, inflammation, and cell survival.
Purpose of the Study:
- To identify TWEAK as an inducer of constitutive NF-kappaB activation.
- To elucidate the sequential regulation of NF-kappaB activation pathways by TWEAK.
- To investigate the role of Fn14 and TRAF proteins in TWEAK-mediated signaling.
Main Methods:
- Expression cloning to identify TWEAK as an NF-kappaB activator.
- Western blotting and electrophoretic mobility shift assays to analyze NF-kappaB components and DNA binding.
- Analysis of NF-kappaB activation in cells with mutated Fn14 or deficient in TRAF2/TRAF5.
Main Results:
- TWEAK stimulation leads to rapid IkappaBalpha phosphorylation and canonical NF-kappaB activation (p50/RelA).
- TWEAK induces prolonged NF-kappaB activation, transitioning to RelB-containing complexes and processing of NF-kappaB2/p100.
- Fn14 binding site mutations and deficiency in TRAF2/TRAF5 abolish TWEAK-induced NF-kappaB activation and p100 processing.
Conclusions:
- TWEAK is a novel physiological regulator of NF-kappaB activation.
- TWEAK differentially regulates canonical and non-canonical NF-kappaB pathways.
- TRAF2 and TRAF5 are essential for TWEAK-mediated signaling through Fn14.