Albertine Donker

Chapter 1 18 Figure 2. Major pathways of hepcidin regulation R-SMAD SMAD4 P Erythropoietic drive Iron signal Inflammation ERFE, TWSG1, GDF15, ? Cell membrane ? BMPR2 ACVR2A BMP6 HJV TfR 2 HFE ALK2/3 P R-SMAD R-SMAD SMAD4 P Nucleus Hepcidin BMP-RE + Activin B IL6-R sHJV Matriptase-2 IL6 JAK JAK P P P STAT3 STAT3 P P STAT3 STAT3 P STAT3-RE Cytoplasm Hepatocyte LSEC BMP6 Ferritin Tf-Fe 2 On the molecular level, multiple signaling pathways sensing body iron (middle), inflammation (right) and erythropoietic drive (left), control hepcidin synthesis. The BMP/SMAD is the main signaling pathway to regulate the transcription of the HAMP gene encoding hepcidin, in particular inside the hepatocyte. BMP’s are produced by LSECs. The iron-induced signaling cascade inside the hepatocyte is initiated following an increase of circulating TBI and stored iron by the endothelial secretion of BMP6. Together with its co- receptor HJV, BMP6 activates type 1 (ALK 2/3) and type 2 (BMPR2, ACVR2A) BMP receptors, leading to phosphorylation of R-SMAD proteins and the formation of active transcriptional complexes with SMAD4. Efficient iron signaling via the BMP/SMAD pathway to the HAMP gene also requires the hemochromatosis proteins HFE and the activated TfR2. Subsequently, the SMAD4 complex is translocated to the nucleus of the hepatocyte where it activates hepcidin transcription upon binding to BMP-RE. In case of inflammation the cytokine IL6 and activin B induce hepcidin transcription via the JAK/STAT3 signaling pathway and the BMP-SMAD pathway, respectively. The binding of IL6 triggers dimerization of IL6R and activation of JAK-kinases on the membrane of the hepatocyte, with subsequent intracellular phosphorylation of STAT3. This phosphorylated complex is translocated to the nucleus where it activates hepcidin transcription upon binding to STAT-RE in the HAMP promoter. Hepcidin suppression is crucial in conditions of iron deficiency and increased erythropoiesis. The main hepcidin inhibitor responsible for this down-regulation is the transmembrane serine protease 6 (MT2, encoded by TMPRSS6 ) that is able to cleave HJV generating a soluble form of HJV (sHJV) and is mainly expressed in hepatocytes. Other proteins that have been proposed to mediate hepcidin suppression via the BMP/SMAD signaling pathway are ERFE, TWSG1 and GDF15. The signaling pathways of these proteins are unknown. Other erythroid regulators of the hepcidin transcription pathway may exist but still have to be identified.