Inducible TNF Receptor Associated Factor-1 Expression Couples to the Canonical to the Non-Canonical NF-κB pathway in TNF stimulation.

The NF-kB transcription factor mediates the inflammatory response through distinct (canonical and non-canonical) signaling pathways. The mechanisms controlling utilization of either of these pathways are largely unknown. Here we observe that TNF stimulation induces delayed NF-kB2/p100 processing and investigate the coupling mechanism. TNF stimulation induces TNF associated factor (TRAF)-1 that ...
directly binds NF-kB inducing kinase (NIK) and stabilizes it from degradation by disrupting its interaction with TRAF2-cIAP2 ubiquitin ligase complex. We show that TRAF1 depletion prevents TNF-induced NIK stabilization and reduces p52 production. To further examine the interactions of TRAF1 and NIK with NF-kB2/p100 processing, we mathematically modeled TRAF1-NIK as a coupling signaling complex and validated computational inference by siRNA knockdown to show non-canonical pathway activation is dependent not only on TRAF1 induction, but also NIK stabilization by forming TRAF1|NIK complex. Thus, these integrated computational-experimental studies of TNF-induced TRAF1 expression identified TRAF1-NIK as a central complex linking canonical and non-canonical pathways by disrupting the TRAF2-cIAP2 ubiquitin ligase complex. This feed-forward kinase pathway is essential for the activation of non-canonical pathway.
J. Biol. Chem.
Date: Mar. 29, 2013
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