Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1.
Bach1 is a transcriptional repressor of heme oxygenase-1 and beta-globin genes, both of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of Bach1, we expressed wild type and mutated versions of Bach1 together with or without its heterodimer partner MafK in human 293T and GM02063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1, whereas treating cells with hemin resulted in nuclear exclusion of Bach1. While the cadmium-inducible nuclear export signal (NES) of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs was found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated NES dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression.
Suzuki
Hiroshi
H
Department of Biomedical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Tashiro
Satoshi
S
Hira
Shusuke
S
Sun
Jiying
J
Yamazaki
Chikara
C
Zenke
Yukari
Y
Ikeda-Saito
Masao
M
Yoshida
Minoru
M
Igarashi
Kazuhiko
K
D021581:Active Transport, Cell Nucleus; D000409:Alanine / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D050976:Basic-Leucine Zipper Transcription Factors; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D050981:Erythroid-Specific DNA-Binding Factors; D004926:Escherichia coli / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005914:Globins / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D028884:Karyopherins / Q000378:metabolism*; D016350:Leucine Zippers; D050985:MafK Transcription Factor; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013053:Spectrophotometry; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016335:Zinc Fingers; D000097606:Exportin 1 Protein
D000409:Alanine; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D051856:Fanconi Anemia Complementation Group Proteins; D005914:Globins; D005982:Glutathione Transferase; D049452:Green Fluorescent Proteins; D006418:Heme; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D006427:Hemin; D028884:Karyopherins; D050985:MafK Transcription Factor; D008565:Membrane Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C102108:BACH1 protein, human; C494695:MAFK protein, human; C496541:HMOX1 protein, human