Abstract
BMP-SMAD signalling plays a crucial role in numerous biological processes including embryonic development and iron homeostasis. Dysregulation of the iron-regulatory hormone hepcidin is associated with many clinical iron-related disorders. We hypothesised that molecules which mediate BMP-SMAD signalling play important roles in the regulation of iron homeostasis and variants in these proteins may be potential genetic modifiers of iron-related diseases. We examined the role of endofin, a SMAD anchor, and show that knockdown of endofin in liver cells inhibits basal and BMP-induced hepcidin expression along with other BMP-regulated genes, ID1 and SMAD7. We show for the first time, the in situ interaction of endofin with SMAD proteins and significantly reduced SMAD phosphorylation with endofin knockdown, suggesting that endofin modulates hepcidin through BMP-SMAD signalling. Characterisation of naturally occurring SNPs show that mutations in the conserved FYVE domain result in mislocalisation of endofin, potentially affecting downstream signalling and modulating hepcidin expression. In conclusion, we have identified a hitherto unrecognised link, endofin, between the BMP-SMAD signalling pathway, and the regulation of hepcidin expression and iron homeostasis. This study further defines the molecular network involved in iron regulation and provides potential targets for the treatment of iron-related disorders.
Highlights
The transforming growth factor-β (TGFβ ) family is composed of 33 structurally related growth factors including TGFβ and bone morphogenetic proteins (BMPs) which regulate a wide variety of cellular responses such as proliferation, differentiation and apoptosis[1,2,3,4]
The FYVE domain is responsible for localising endofin to endosomal vesicles which is important for its function in trafficking SMADs to internalised BMP receptors in early endosomes[14]
Previous studies have shown that endofin enhances BMP-SMAD signalling by anchoring SMAD proteins to BMP receptors
Summary
The transforming growth factor-β (TGFβ ) family is composed of 33 structurally related growth factors including TGFβ and bone morphogenetic proteins (BMPs) which regulate a wide variety of cellular responses such as proliferation, differentiation and apoptosis[1,2,3,4]. TGFβ signalling is mediated by the SMAD anchor for receptor activation (SARA) while signalling in the BMP pathway is mediated by the endosome-associated FYVE-domain protein (endofin)[14]. BMP-SMAD signalling is central to iron homeostasis through the regulation of hepcidin, a peptide hormone encoded by the HAMP gene, responsible for regulating serum iron levels. Hepcidin regulation is tightly controlled at many levels This includes BMPs which bind to trans-membrane BMP receptors, facilitated by hemojuvelin (HJV), a co-receptor that enhances BMP signalling to induce the transcription of HAMP, together with other BMP-regulated genes such as ID1 (inhibitor of DNA binding protein 1) and SMAD7 (SMAD family member 7)[20,21,22]. Our finding further defines the molecular network involved in iron regulation, providing potential targets for the treatment of iron-related disorders and possibly BMP-associated disorders
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