The role of ubiquitination in BMP signaling and iron homeostasis

• Applicant: Dr. Lisa Schrader
• Subject Area: Cell Biology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544565191

Disturbances within the hepcidin-ferroportin axis and iron homeostasis are associated with both iron overload- and iron deficiency-related diseases and are significant causes of morbidity and mortality. The hepatic hormone hepcidin is the central regulator of systemic iron homeostasis. Hepcidin downregulates the cell surface expression ferroportin on enterocytes, macrophages, hepatocytes and erythrocytes and limits iron release into the circulation from both the gastrointestinal tract and iron stores in the liver and spleen. In iron overload diseases, the relative or absolute deficiency of hepcidin results in increased cell surface expression of ferroportin, while the overexpression of hepcidin leads to reduced iron availability and causes anemia. Hepcidin is produced in the liver in response to circulating and stored iron and inflammatory mediators such as Interleukin (IL)-6. At the transcriptional level, the expression of hepcidin is controlled by the bone morphogenetic protein (BMP) signaling pathway. While it is known that the ubiquitin system regulates the expression of proteins involved in BMP signaling and the induction of hepcidin expression, the specific enzymes that are involved in this process and their precise function have yet to be determined. The main goal of this research proposal is to understand and characterize the role of ubiquitination in the regulation of the BMP-hepcidin-ferroportin signaling pathway. The objectives of the proposed experiments are to elucidate the mechanism by which specific E3 enzymes regulate the expression of hepcidin and iron homeostasis. In addition to the in vitro characterization, the functional significance of novel regulators will be investigated in animal studies in vivo. Identifying and understanding the molecular details of how the BMP signaling pathway is regulated by ubiquitination will lay the groundwork for the development of novel strategies to treat iron related diseases.

• DFG Programme: Research Grants