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.
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 ( approximately 1,500-2,000 kDa), which we designate ASK1 signalosome. Upon H(2)O(2) 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, H(2)O(2)-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.
Noguchi
Takuya
T
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, Japan.
Takeda
Kohsuke
K
Matsuzawa
Atsushi
A
Saegusa
Kaoru
K
Nakano
Hiroyasu
H
Gohda
Jin
J
Inoue
Jun-Ichiro
J
Ichijo
Hidenori
H
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; C494631:VAC14 protein, human