Genetics and cell biology

Regulation of iron metabolism

Regulation of iron metabolism Unit studies the systemic iron regulation in physiologic conditions and in human disorders. The hepcidin/ferroportin axis regulates iron absorption and recycling.

The group has identified a new level of hepcidin control by the immunophilin, RNA-binding protein FKBP12, which binds to and inhibits the BMP receptor ALK2. We are exploring the FKBP12 mechanistic function, its relationship with homo and heterodimeric receptors and the effect of its liver selective inactivation.

Investigating the crosstalk between hepcidin and erythropoiesis we have defined the role of the second transferrin receptor (TFR2). Homologous to the ubiquitous TFR1, TFR2 is expressed only in hepatocytes and erythroid precursors. Hepatic TFR2 contributes to hepcidin activation and its inactivation leads to hemochromatosis. Our results suggest that TFR2 acts as a brake of EPO signaling. Erythroid TFR2, which interacts with Erythropoietin receptor (EPOR), controls the production of erythrocytes and that its bone marrow deletion causes erythropoietin-independent erythrocytosis.

Research activity

The aim of current studies is to understand the molecular mechanism of TFR2-mediated hepcidin upregulation, the molecular interaction of TFR2-EPOR in erythropoiesis and to exploit the new knowledge to boost erythroid response in congenital and acquired hypoproliferative anemias and thalassemia.

Another line of investigation is focused on NCOA4, the cargo protein for ferritin degradation in the process of ferritinophagy. By transplanting bone marrow Ncoa4 null cells to wild type recipient mice and vice versa we are trying to define the contribution of NCOA4 to the physiology of erythroid and macrophage cells.