Inducible Tumor Necrosis Factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation

Sanjeev Choudhary, Mridul Kalita, Ling Fang, Kershaw V. Patel, Bing Tian, Yingxin Zhao, Chukwudi B. Edeh, Allan R. Brasier

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The NF-κB 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-κB2/p100 processing and investigate the coupling mechanism. TNF stimulation induces TNF-associated factor-1 (TRAF-1) that directly binds NF-κB-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-κB2/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.

Original languageEnglish (US)
Pages (from-to)14612-14623
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number20
DOIs
StatePublished - May 17 2013

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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
TNF Receptor-Associated Factor 1
Phosphotransferases
Tumor Necrosis Factor-alpha
Ligases
Ubiquitin
Stabilization
TNF Receptor-Associated Factor 2
Chemical activation
Processing
Small Interfering RNA
Transcription Factors
Degradation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Inducible Tumor Necrosis Factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation. / Choudhary, Sanjeev; Kalita, Mridul; Fang, Ling; Patel, Kershaw V.; Tian, Bing; Zhao, Yingxin; Edeh, Chukwudi B.; Brasier, Allan R.

In: Journal of Biological Chemistry, Vol. 288, No. 20, 17.05.2013, p. 14612-14623.

Research output: Contribution to journalArticle

Choudhary, Sanjeev ; Kalita, Mridul ; Fang, Ling ; Patel, Kershaw V. ; Tian, Bing ; Zhao, Yingxin ; Edeh, Chukwudi B. ; Brasier, Allan R. / Inducible Tumor Necrosis Factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 20. pp. 14612-14623.
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