Journal article
Gain-of-function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway
American journal of hematology, v 95(2), pp 188-197
Feb 2020
PMID: 31737919
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the PIEZO1 gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca2+ influx and suppression of HAMP expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain-of-function mutants (R2456H and R2488Q), we highlight altered expression of a few genes/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca2+ compared to WT, which was correlated to increased phosphorylation of ERK1/2, inhibition of the BMP-SMADs pathway, and suppression of HAMP transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1/2 phosphorylation, reduced the phosphorylation of ERK1/2 with the consequent increased phosphorylation of SMAD1/5/8, confirming the link between the two pathways. Another "proof of concept" for the mechanism that links PIEZO1 to HAMP regulation was obtained by mimicking PIEZO1 activation by cell Ca2+ overload, by the Ca2+ ionophore A23187. There was strong down-regulation of HAMP gene expression after this Ca2+ overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron-loading anemias.
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Details
- Title
- Gain-of-function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway
- Creators
- Immacolata Andolfo - University of Naples Federico IIBarbara Eleni Rosato - University of Naples Federico IIFrancesco Manna - Ceinge Biotecnologie Avanzate (Italy)Gianluca De Rosa - University of Naples Federico IIRoberta Marra - University of Naples Federico IIAntonella Gambale - University of Naples Federico IIDomenico Girelli - University of VeronaRoberta Russo - University of Naples Federico IIAchille Iolascon - University of Naples Federico II
- Publication Details
- American journal of hematology, v 95(2), pp 188-197
- Publisher
- Wiley
- Number of pages
- 10
- Grant note
- 3978026 / European Hematology Association Bando Star Linea 1 - JUNIOR PRINCIPAL INVESTIGATOR GRANTS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000501365500001
- Scopus ID
- 2-s2.0-85076378489
- Other Identifier
- 991022004956304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Hematology