Dynamic Cytoplasmic Anchoring of the Transcription Factor Bach1 by Intracellular Hyaluronic Acid Binding Protein IHABP

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Abstract
Bach1 functions as a transcriptional repressor of heme oxygenase-1 (HO-1) and the β-globin genes. The enhancer regions of these genes contain multiple Maf recognition elements (MAREs) to which Bach1 can bind. Previous studies have shown that increased levels of heme and cadmium induce the nuclear export of Bach1, resulting in cytoplasmic accumulation. By means of a yeast two hybrid screening using Bach1 as bait, we identified the intracellular hyaluronic acid binding protein (IHABP) as a potential regulator of Bach1. IHABP is a microtubule-associated protein that may regulate the organization of the cytoskeletal network. A series of domain analyses revealed that a region of Bach1 previously implicated in cytoplasmic accumulation was necessary for IHABP-binding. A C-terminal region of IHABP was necessary for Bach1-binding. Overexpressed Bach1 colocalized with IHABP in the cytoplasm, forming fiber-like structures on microtubules. Fluorescence recovery after photobleaching (FRAP) analysis revealed a dynamic nature of the Bach1-IHABP interaction in living cells. The repression of HO-1 reporter activity by Bach1 was attenuated by co-transfecting IHABP in a dose-dependent manner. Moreover, the overexpression of IHABP induced the endogenous HO-1 gene in NIH3T3 cells. The overall results suggest that IHABP regulates the subcelluar localization of Bach1 in order to fine-tune transactivation of Bach1 target genes such as HO-1.

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