Both amino- and carboxyl-terminal domains of TRAF3 negatively regulate NF-κB activation induced by OX40 signaling

Akifumi Takaori-Kondo, Toshiyuki Hori, Keiko Fukunaga, Rinpei Morita, Shin Kawamata, Takashi Uchiyama

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

OX40 is a member of the tumor necrosis factor receptor (TNF-R) superfamily. We observed that overexpression of OX40 activated NF-κB, which was inhibited by dominant negative forms of TRAF2, NF-κB-inducing kinase (NIK), and IkappaB kinase (IKK) α. This indicates that OX40 signaling leads to NF-κB activation through the same cascade as TNF-R2. We then investigated the negative regulatory function of TRAF3 on OX40-induced NF-κB activation. TRAF3 blocked OX40-, TRAF2-induced NF-κB activation, but not NIK- and IKKα-induced NF-κB activation, indicating that TRAF3 blocks the pathway between TRAF2 and NIK. C-terminal deletion mutants as well as the N-terminal deletion mutant of TRAF3 inhibited NF-κB activation induced by OX40 or TRAF2. Since TRAF3 bound to OX40 through the C-terminal TRAF domain, the C-terminal domain is likely to work as a dominant negative mutant to compete the recruitment of TRAF2 to the receptor, which transmits the signal from OX40 to the downstream, NIK kinase. On the other hand, the N-terminal domain of TRAF3 seems to affect the downstream of TRAF2 binding. Thus, it is suggested that TRAF3 actively inhibits NF-κB activation induced by OX40. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)856-863
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume272
Issue number3
DOIs
Publication statusPublished - 2000 Jun 16
Externally publishedYes

Fingerprint

TNF Receptor-Associated Factor 3
TNF Receptor-Associated Factor 2
Chemical activation
Phosphotransferases
I-kappa B Kinase
Receptors, Tumor Necrosis Factor, Type II
Tumor Necrosis Factor Receptors

Keywords

  • IKKα
  • NF-κB
  • NIK
  • OX40
  • TRAF2
  • TRAF3

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Both amino- and carboxyl-terminal domains of TRAF3 negatively regulate NF-κB activation induced by OX40 signaling. / Takaori-Kondo, Akifumi; Hori, Toshiyuki; Fukunaga, Keiko; Morita, Rinpei; Kawamata, Shin; Uchiyama, Takashi.

In: Biochemical and Biophysical Research Communications, Vol. 272, No. 3, 16.06.2000, p. 856-863.

Research output: Contribution to journalArticle

Takaori-Kondo, Akifumi ; Hori, Toshiyuki ; Fukunaga, Keiko ; Morita, Rinpei ; Kawamata, Shin ; Uchiyama, Takashi. / Both amino- and carboxyl-terminal domains of TRAF3 negatively regulate NF-κB activation induced by OX40 signaling. In: Biochemical and Biophysical Research Communications. 2000 ; Vol. 272, No. 3. pp. 856-863.
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AB - OX40 is a member of the tumor necrosis factor receptor (TNF-R) superfamily. We observed that overexpression of OX40 activated NF-κB, which was inhibited by dominant negative forms of TRAF2, NF-κB-inducing kinase (NIK), and IkappaB kinase (IKK) α. This indicates that OX40 signaling leads to NF-κB activation through the same cascade as TNF-R2. We then investigated the negative regulatory function of TRAF3 on OX40-induced NF-κB activation. TRAF3 blocked OX40-, TRAF2-induced NF-κB activation, but not NIK- and IKKα-induced NF-κB activation, indicating that TRAF3 blocks the pathway between TRAF2 and NIK. C-terminal deletion mutants as well as the N-terminal deletion mutant of TRAF3 inhibited NF-κB activation induced by OX40 or TRAF2. Since TRAF3 bound to OX40 through the C-terminal TRAF domain, the C-terminal domain is likely to work as a dominant negative mutant to compete the recruitment of TRAF2 to the receptor, which transmits the signal from OX40 to the downstream, NIK kinase. On the other hand, the N-terminal domain of TRAF3 seems to affect the downstream of TRAF2 binding. Thus, it is suggested that TRAF3 actively inhibits NF-κB activation induced by OX40. (C) 2000 Academic Press.

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