Increased systemic iron levels induce the expression of hepcidin via TfR/Hfe (IMAGE)
Caption
Saturation of TfR1 leads to the dissociation of Hfe and the binding of the alter to the TfR2, which in turn influences the binding of BMP6 to its receptors on the membrane. Increased liver iron concentration induces the expression of the BMP6 gene, forming BMP6 proteins, which bind to the BMP receptors (ALK2). When bound to BMP6, the receptors recruit SMAD proteins and phosphorylation of SMAD1/5/8-SMAD4 complex mobilizes to the nucleus, activating the expression of hepcidin. Inflammatory signals via IL-6 through the JAK-STAT cascade induce the expression of the Hepcidin gene (HAMP). Higher EPO and HIF lead to the secretion of ERFE from erythroid precursor cells, which attenuates the BMP6 signaling cascade via GDF15/TWSG1. In the absence of BMP6, TMPRSS6 binds to ALK2, inhibiting the hepcidin signaling cascade. BMP6, bone morphogenic protein 6; EPO, erythropoietin; ERFE, erythroferrone; Erk, extracellular signal-regulated kinase; GDF15, growth differentiation factor15, HAMP, hepcidin antimicrobial peptide; Hfe, hemochromatosis gene; HIF, hypoxia-induced factor; IL-6, interleukin 6; JAK-STAT, Janus kinase/signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; sHJV, soluble hemojuvelin ; SMAD, mothers against decapentaplegic; TfR1/2, Transferrin receptor; TMPRSS6, transmembrane serine protease 6; TWSG1, twisted gastrulation factor1.
Credit
Akila Prashant
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