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Molecular and Cellular Biology, September 2001, p. 6139-6150, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6139-6150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Regulation of the Yeast Yap1p Nuclear Export Signal Is Mediated by Redox Signal-Induced Reversible Disulfide Bond Formation

Shusuke Kuge,1,2,* Minetaro Arita,1 Asako Murayama,1 Kazuhiro Maeta,3 Shingo Izawa,3 Yoshiharu Inoue,3 and Akio Nomoto1

Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku Tokyo 113-0033,1 Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578,2 and Laboratory of Molecular Microbiology, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011,3 Japan

Received 22 December 2000/Returned for modification 15 February 2001/Accepted 22 June 2001

Yap1p, a crucial transcription factor in the oxidative stress response of Saccharomyces cerevisiae, is transported in and out of the nucleus under nonstress conditions. The nuclear export step is specifically inhibited by H2O2 or the thiol oxidant diamide, resulting in Yap1p nuclear accumulation and induction of transcription of its target genes. Here we provide evidence for sensing of H2O2 and diamide mediated by disulfide bond formation in the C-terminal cysteine-rich region (c-CRD), which contains 3 conserved cysteines and the nuclear export signal (NES). The H2O2 or diamide-induced oxidation of the c-CRD in vivo correlates with induced Yap1p nuclear localization. Both were initiated within 1 min of application of oxidative stress, before the intracellular redox status of thioredoxin and glutathione was affected. The cysteine residues in the middle region of Yap1p (n-CRD) are required for prolonged nuclear localization of Yap1p in response to H2O2 and are thus also required for maximum transcriptional activity. Using mass spectrometry analysis, the H2O2-induced oxidation of the c-CRD in vitro was detected as an intramolecular disulfide linkage between the first (Cys598) and second (Cys620) cysteine residues; this linkage could be reduced by thioredoxin. In contrast, diamide induced each pair of disulfide linkage in the c-CRD, but in this case the cysteine residues in the n-CRD appeared to be dispensable for the response. Our data provide evidence for molecular mechanisms of redox signal sensing through the thiol-disulfide redox cycle coupled with the thioredoxin system in the Yap1p NES.

* Corresponding author. Mailing address: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aza-aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan. Phone: 81-22-217-6872. Fax: 81-22-217-6872. E-mail: skuge{at}mail.pharm.tohoku.ac.jp.

Molecular and Cellular Biology, September 2001, p. 6139-6150, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6139-6150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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