Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death

Takuya Noguchi, Kohsuke Takeda, Atsushi Matsuzawa, Kaoru Saegusa, Hiroyasu Nakano, Jin Gohda, Jun Ichiro Inoue, Hidenori Ichijo

Research output: Contribution to journalArticlepeer-review

163 Citations (Scopus)

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) plays a pivotal role in oxidative stress-induced cell death. Reactive oxygen species disrupt the interaction of ASK1 with its cellular inhibitor thioredoxin and thereby activates ASK1. However, the precise mechanism by which ASK1 freed from thioredoxin undergoes oligomerization-dependent activation has not been fully elucidated. Here we show that endogenous ASK1 constitutively forms a high molecular mass complex including Trx (∼1,500-2,000 kDa), which we designate ASK1 signalosome. Upon H2O2 treatment, the ASK1 signalosome forms a higher molecular mass complex at least in part because of the recruitment of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. Consistent with our previous findings that TRAF2 and TRAF6 activate ASK1, H2O2-induced ASK1 activation and cell death were strongly reduced in the cells derived from Traf2-/- and Traf6-/- mice. A novel signaling complex including TRAF2, TRAF6, and ASK1 may thus be the key component in oxidative stress-induced cell death.

Original languageEnglish
Pages (from-to)37033-37040
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number44
DOIs
Publication statusPublished - 2005 Nov 4

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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