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Mol. Cell. Biol. doi:10.1128/MCB.02415-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Heme induces ubiquitination and degradation of the transcription factor Bach1

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

^* To whom correspondence should be addressed. Email: igarak{at}mail.tains.tohoku.ac.jp.

	Abstract

The transcription repressor Bach1 is a sensor and an effecter 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 NIH3T3 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. Poly-ubiquitination 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 NIH3T3 cells. HOIL-1 stimulated the poly-ubiquitination 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 poly-ubiquitination and degradation of Bach1.

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