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Gain‐of‐function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway
Author(s) -
Andolfo Immacolata,
Rosato Barbara Eleni,
Manna Francesco,
De Rosa Gianluca,
Marra Roberta,
Gambale Antonella,
Girelli Domenico,
Russo Roberta,
Iolascon Achille
Publication year - 2020
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.25683
Subject(s) - hamp , piezo1 , hepcidin , phosphorylation , microbiology and biotechnology , mutant , intracellular , biology , smad , signal transduction , chemistry , medicine , endocrinology , mechanosensitive channels , ion channel , gene , biochemistry , immunology , receptor , inflammation
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 Ca 2+ 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 Ca 2+ 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 Ca 2+ overload, by the Ca 2+ ionophore A23187. There was strong down‐regulation of HAMP gene expression after this Ca 2+ 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.