Heme Metabolism in Stress Response

Abstract

Heme and its metabolism fulfill significant roles in many homeostatic and adaptative reactions. For example, heme (protein) senses oxygen concentration to regulate hypoxia response genes such as erythropoietin, and free heme, a proxidant, controls levels of several oxidative stress response proteins as well as that of a few enzymes in the heme metabolic pathway. Heme oxygenase (HO) is the key enzyme in heme catabolism, which degrades heme to Fe, CO, and biliverdin. CO is known as a gaseous messenger in the vascular and nervous systems. Biliverdin is rapidly converted to bilirubin, whose antioxidative effect is proposed to protect cells against reactive oxygen species. HO-1, the inducible isozyme of HO, is induced not only by its substrate heme, but also NO, metals, hypoxia, and various other stimuli. Studies on HO-1 deficiency indicate that induction of HO-1 is essential to homeostasis, at least in humans. Heme response elements (HREs), which mediate the induction of HO-1 expression by heme, are identified in enhancer regions of the mouse HO-1 gene. HRE shares a nucleotide sequence with the Maf recognition element (MARE). A transcriptional activator, Nrf2, has been shown to participate in HO-1 induction by several stimuli, including heme via HRE. A heme-binding transcription factor such as yeast Hapl had been supposed to also exist in vertebrates, however, no such factor had been identified. Recently, we found that a mammalian transcription repressor, Bach1, directly binds heme, and that the DNA binding activity of Bach1 is negatively regulated by heme. Bach1 is capable of competing the binding to MARE with activators including Nrf2, therefore, HO-1 and other stress response genes bearing MARE may be regulated by heme via the MARE-binding transcription factors. Further analyses on the gene regulatory mechanism by heme would help us to understand the stress response system, especially against oxidative stress.