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Molecular and Cellular Biology, December 2007, p. 8152-8163, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00227-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Thioredoxin and TRAF Family Proteins Regulate Reactive Oxygen Species-Dependent Activation of ASK1 through Reciprocal Modulation of the N-Terminal Homophilic Interaction of ASK1{triangledown} ,{dagger}

Go Fujino,1 Takuya Noguchi,1 Atsushi Matsuzawa,1 Shota Yamauchi,1 Masao Saitoh,2 Kohsuke Takeda,1 and Hidenori Ichijo1*

Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, Japan Science and Technology Corporation and Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Center of Excellence (COE) program, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,1 Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan2

Received 9 February 2007/ Returned for modification 18 April 2007/ Accepted 1 August 2007

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase family, plays pivotal roles in reactive oxygen species (ROS)-induced cellular responses. In resting cells, endogenous ASK1 constitutively forms a homo-oligomerized but still inactive high-molecular-mass complex including thioredoxin (Trx), which we designated the ASK1 signalosome. Upon ROS stimulation, the ASK1 signalosome unbinds from Trx and forms a fully activated higher-molecular-mass complex, in part by recruitment of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. However, the precise mechanisms by which Trx inhibits and TRAF2 and TRAF6 activate ASK1 have not been elucidated fully. Here we demonstrate that the N-terminal homophilic interaction of ASK1 through the N-terminal coiled-coil domain is required for ROS-dependent activation of ASK1. Trx inhibited this interaction of ASK1, which was, however, enhanced by expression of TRAF2 or TRAF6 or by treatment of cells with H2O2. Furthermore, the H2O2-induced interaction was reduced by double knockdown of TRAF2 and TRAF6. These findings demonstrate that Trx, TRAF2, and TRAF6 regulate ASK1 activity by modulating N-terminal homophilic interaction of ASK1.

* Corresponding author. Mailing address: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-5841-4858. Fax: 81-3-5841-4798. E-mail: ichijo{at}mol.f.u-tokyo.ac.jp

{triangledown} Published ahead of print on 27 August 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2007, p. 8152-8163, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00227-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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