Schematic representation of mechanisms activating hepcidin transcription.
Central part – BMP6 and BMP2 activate type I and II receptors, interacting with the co-receptor hemojuvelin on hepatocyte plasma membrane. This triggers the phosphorylation of SMAD1/5/8, which interacts with SMAD4; the transcriptional SMAD complex translocates to the nucleus to activate transcription of the HAMP gene, which encodes hepcidin. ERFE can sequester BMP6 and other BMPs.
Left side (potential role of HFE and TfR2) – HFE binds TfR1 in competition with Tf-Fe2. High Tf-Fe2 levels displace HFE, which is then free to bind TfR2. It is hypothesized that the HFE-TfR2 complex activates hepcidin, but the molecular mechanisms are unclear (indicated by the question mark).
Right side – IL-6, increased in inflammation, interacts with its receptor (IL-6R) to phosphorylate STAT3, which in turn interacts with the HAMP promoter to activate hepcidin transcription.