Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from binding to the BMP type I receptor ALK3

Abstract

The authors dissect the transcriptional regulatory pathway by which the iron regulatory hormone hepcidin is suppressed by erythroferrone in response to erythropoietin.

Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

“…The current model suggests that ALK2 is mainly involved in BMP6-dependent hepcidin upregulation in conditions of iron overload 4 and is inhibited by FKBP12, 5 whereas ALK3 maintains basal hepcidin expression 4 and signals preferentially in response to BMP2. 6 , 7 Hereditary hemochromatosis (HH), characterized by iron overload due to inappropriately low hepcidin production, is caused by mutations in HFE , the second transferrin receptor ( TFR2 ), hemojuvelin ( HJV ) and hepcidin ( HAMP ). HJV is a BMP co-receptor that activates the BMP-SMAD pathway and hepcidin expression.…”

Cell‐type‐specific insights into iron regulatory processes

“…134 This observation is supported by the evidence that the BMP2-BMP6 heterodimer can stimulate hepcidin in cultured hepatocytes. 134,135 However, the functional role of such heterodimers in vivo needs to be elucidated.…”

Drugging erythroferrone to treat anemias

“…Moreover, the costs associated with NGS can be prohibitive in a diagnostic setting; thus, batch testing would be required to reduce the expense associated with testing each sample separately, adding to the delay in obtaining results. In comparison, SS is fast and inexpensive, although it has a mutation detection limit of 10% to 20%, 7,8 which negates its applicability in low-level mutation testing. Before NGS-based assays can be adopted into mainstream diagnostics, these issues will need to be addressed by each institution that intends to implement them for the purpose of KD mutation testing.…”

“…Here, the relevant physiological ligand may be the BMP2/6 heterodimer, which could be the species entrapped by ERFE (see figure), as suggested by others. 7 The avidity of the interaction between ERFE and these BMPs may be further strengthened by the multimeric structure of ERFE (in this regard, behaving similarly to adiponectin 8 ), with multimerization promoted by the interactions between the globular C-terminal regions.…”

“…The functional significance of the single-chain activity is evident for PK and FXII because this can drive autoactivation and stimulate a cascade without the requirement of an exogenous protease to cleave the activation loop. Thus, PK can be activated by a nonproteolytic mechanism via prolyl-carboxypeptidase 7 or heat shock protein 90 8 without the need for FXII. Perturbation of the PK protein structure is sufficient to release the clutch and engage the single-chain low-gear…”