Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1

Abstract

Bach1 is a transcriptional repressor of heme oxygenase-1 and β-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

Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the haem binding properties of the protein

“…In contrast with globins or cytochromes that provide non-cysteine axial ligands and induce a bathochromic shift of the Soret band of free haemin, the shift observed in our experiments with the truncated peptide, but not with the fulllength domain, agrees with cysteine axial ligation to ferric haem. Such a cysteine may be contributed by the HRM (haem-regulatory motif)-like sequence (-CPFH-) of the peptide [34,35,39]. These results are in agreement with results of TOCSY experiments.…”

“…No increases of the baseline towards shorter wavelengths were apparent, excluding any aggregation problem detected at higher concentrations (see above). The hypsochromic shift of the Soret band has already been observed by interaction between haem and a thiolate axial ligand [34,35].…”

Non-random subcellular distribution of variant EKLF in erythroid cells

“…It is possible that there may exist such an analogous anchor(s) for EKLF in the erythroid cell. Of more potential relevance to red cell biology, heme has been shown to affect the nuclear-cytoplasmic shuttling of Bach1 [49], a heterodimer partner of MafK that is known to be replaced by the critical p45/ NFE2 activator upon erythroid differentiation [50]. However, inhibition of heme synthesis by succinylacetone had no effect upon EKLF localization (unpublished observations).…”

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

“…No single HRM (CP) motif is indispensable for heme regulation of Bach1, indicating that there is functional redundancy among the HRM (CP) motifs [22]. The three heme binding motifs of Bach1 function as heme-activated nuclear export signals, suggesting that Bach1-mediated gene expression is at least partially mediated by the regulation of Bach1 subcellular localization [77,83,84].…”