UNRAVELING HFE-INTERACTION PARTNERS AND SIGNALLING: IMPACT ON CELLULAR IRON HOMEOSTASIS

Tissue iron overload is the most common side effect after RBC transfusion. As the human body has no regulatory mechanisms to excrete iron, long-term transfusion inevitably produces the clinical problem of iron overload. The patient’s underlying disease determines iron distribution among cell types. Overall, iron accumulation in parenchymal cells is considered more toxic than that in cells of the reticuloendothelial system.

We hypothesize that sensitivity of a cell to iron-induced toxicity is determined by the net outcome of transferrin-bound iron (TBI) and non-transferrin-bound iron (NTBI) uptake rates, capacity of iron export, regulation of iron deposition into ferritin and capacity of the cell to initiate a proper antioxidant defense. The hereditary hemochromatosis protein (HFE) is implicated to have a regulatory role in a number of these processes, including import of TBI and NTBI through an interplay with TfR2, TfR1 and NTBI-transporter ZIP14. HFE also inhibits iron release from macrophages either by systemic control of ferroportin via induction of hepatic hepcidin production and/or by direct cell-specific regulation of its expression.

We aim to identify HFE-dependent regulatory pathways involved in cellular iron homeostasis, and how these cell-specific and/or systemic regulatory pathways contribute to transfusion and iron overload-related toxicity. So far, we have successfully generated hepatocyte cell lines overexpressing HFE tagged with miniturbo-ID for biotin proximity labeling. Currently, we are validating our cell systems and plan to identify downstream signaling and complex partners of HFE under conditions of iron overload and relate the identified proteins to their role in iron homeostasis and toxicity.