Transcriptional activation of hepcidin by the microphthalmia/transcription factor E family

Hepcidin negatively regulates the circulating iron levels by inhibiting the intestinal absorption of iron as well as iron release from macrophages. Hepcidin activity is largely determined by its expression, which is regulated at the transcriptional level. Hepcidin transcription is induced not only by the iron status-related bone morphogenetic protein (BMP)-2/6, but also by inflammatory cytokines, such as interleukin (IL)-1β and IL-6. The present study reveals that the microphthalmia (MiT)/transcription factor E (TFE) family members are novel regulators of hepcidin transcription. Melanocyte-inducing transcription factor (MITF)-A, a member of the MiT/TFE family, was identified as a positive regulator of hepcidin transcription via stimulus screening for transcription regulators. An E-box (5'-CATGTG-3') spanning nt-645 to nt-640 of the murine hepcidin promoter was identified as an MITF-A-responsive element. Responsiveness to MITF-A on hepcidin transcription decreased when the cells were stimulated with BMP2 or IL-1β. These results suggest a functional interaction between the MITF pathway and BMP- or IL-1β-mediated signaling. TFEB and TFE3, members of the MiT/TFE family, also stimulated hepcidin transcription, but the main region responsible for hepcidin transcription was distinct from that induced by MITF-A. The region spanning nt-581 to nt-526 was involved in TFEB/TFE3-mediated hepcidin transcription. Considering that members of the MiT/TFE family act as regulators of starvation-induced lysosomal biogenesis, hepcidin expression may be controlled by additional pathways apart from those identified so far.