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Molecular and Cellular Biology, October 2007, p. 6962-6971, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.02415-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Heme Induces Ubiquitination and Degradation of the Transcription Factor Bach1{triangledown}

Yukari Zenke-Kawasaki,1,2 Yoshihiro Dohi,1 Yasutake Katoh,1 Tsuyoshi Ikura,1 Masae Ikura,1 Toshimasa Asahara,2 Fuminori Tokunaga,3 Kazuhiro Iwai,3 and Kazuhiko Igarashi1*

Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan,1 Department of Surgery, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Hiroshima 734-8551, Japan,2 Department of Molecular Cell Biology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Osaka 545-8585, Japan3

Received 26 December 2006/ Returned for modification 5 February 2007/ Accepted 23 July 2007

The transcription repressor Bach1 is a sensor and effector of heme that regulates the expression of heme oxygenase 1 and globin genes. Heme binds to Bach1, inhibiting its DNA binding activity and inducing its nuclear export. We found that hemin further induced the degradation of endogenous Bach1 in NIH 3T3 cells, murine embryonic fibroblasts, and murine erythroleukemia cells. In contrast, succinylacetone, an inhibitor of heme synthesis, caused accumulation of Bach1 in murine embryonic fibroblasts, indicating that physiological levels of heme regulated the Bach1 turnover. Polyubiquitination and rapid degradation of overexpressed Bach1 were induced by hemin treatment. HOIL-1, an ubiquitin-protein ligase which recognizes heme-bound, oxidized iron regulatory protein 2, was found to bind with Bach1 when both were overexpressed in NIH 3T3 cells. HOIL-1 stimulated the polyubiquitination of Bach1 in a purified in vitro ubiquitination system depending on the intact heme binding motifs of Bach1. Expression of dominant-negative HOIL-1 in murine erythroleukemia cells resulted in higher stability of endogenous Bach1, raising the possibility that the heme-regulated degradation involved HOIL-1 in murine erythroleukemia cells. These results suggest that heme within a cell regulates the polyubiquitination and degradation of Bach1.

* Corresponding author. Mailing address: Department of Biochemistry, Tohoku University School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan. Phone: 81-22-717-7595. Fax: 81-22-717-7598. E-mail: igarak{at}mail.tains.tohoku.ac.jp

{triangledown} Published ahead of print on 6 August 2007.

Molecular and Cellular Biology, October 2007, p. 6962-6971, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.02415-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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