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Vol. 20, Issue 16, 3628-3637, August 15, 2009

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REDOX Reaction at ASK1-Cys250 Is Essential for Activation of JNK and Induction of Apoptosis

Philippe J. Nadeau^*, Steve J. Charette, and Jacques Landry^*

*Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Québec, Canada, G1R 2J6; and Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (Centre de recherche Hôpital Laval), Pavillon Mallet (bureau M2689), Institut universitaire de cardiologie et de pneumologie de Québec (Hôpital Laval), Québec, Canada, G1V 4G5

Submitted March 13, 2009; Revised June 3, 2009; Accepted June 22, 2009
Monitoring Editor: Donald D. Newmeyer

ASK1 cysteine oxidation allows JNK activation upon oxidative stress. Trx1 negatively regulates this pathway by reducing the oxidized cysteines of ASK1. However, precisely how oxidized ASK1 is involved in JNK activation and how Trx1 regulates ASK1 oxidoreduction remains elusive. Here, we describe two different thiol reductase activities of Trx1 on ASK1. First, in H₂O₂-treated cells, Trx1 reduces the various disulfide bonds generated between cysteines of ASK1 by a rapid and transient action. Second, in untreated cells, Trx1 shows a more stable thiol reductase activity on cysteine 250 (Cys250) of ASK1. After H₂O₂ treatment, Trx1 dissociates from Cys250, which is not sufficient to activate the ASK1-JNK pathway. Indeed, in untreated cells, a Cys250 to alanine mutant of ASK1 (C250A), which cannot bind Trx1, does not constitutively activate JNK. On the other hand, in H₂O₂-treated cells, this mutant (C250A) fails to activate JNK and does not induce apoptosis, although it remains fully phosphorylated on Threonine 838 (Thr838) in its activation loop. Overall, our data show that Cys250 is essential for H₂O₂-dependent signaling downstream from ASK1 but at a step subsequent to the phosphorylation of ASK1 Thr838. They also clarify the thiol reductase function of Trx1 on ASK1 activity.

Address correspondence to: Philippe Nadeau (philippe.nadeau.1{at}ulaval.ca).

Abbreviations used: ASK1, apoptosis signal-regulated kinase 1; Trx1, thioredoxin-1; DBM, disulfide-bonded multimer; JNK, c-Jun NH₂-terminal kinase; TNF, tumor necrosis factor; TRAF, tumor receptor-associated factor.

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