Gain‐of‐function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway

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 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.

YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation

“…PIEZO1 knockdown reduced Yoda1-induced ERK1/2 and p38 MAPK phosphorylation but did not affect AKT phosphorylation ( Figure 3E). Supporting our results, a previous report revealed that gain-of-function mutations in PIEZO1 increased Ca 2+ concentrations with ERK1/2 activation, indicating that the PIEZO1 channel activates intracellular signaling [51]. These results suggest that PIEZO1 may function as an ion channel and its expression is involved in agonist-dependent ERK1/2 and p38 MAPK activation in OSCC cells.…”

A novel PIEZO1 mutation in a patient with dehydrated hereditary stomatocytosis: a case report and a brief review of literature

“…Our recent genotype-phenotype correlation analysis on 29 PIEZO1-patients demonstrated that most of severely affected patients carried mutations in the pore domain, responsible of the ion passage, while patients showing a less severe phenotype carried mutations in the nonpore domain [7]. In accordance to this finding, the patients here described, both proband and father, showed a mild phenotype and the absence of iron overload [20].…”

“…Splenectomy is thus contraindicated in this condition. In addition, in patients with DHS iron metabolism should be regularly checked for the risk of developing sever hepatic iron overload [20] (Table 2).…”

Congenital Hemolytic Anemias: Is There a Role for the Immune System?

“…Further evidence for the interplay between iron and inflammation comes from studies in DHSt, where hepcidin levels were decreased and erythroferrone (ERFE), the negative regulator of hepcidin, slightly increased. In patients with gain-of-function mutations in PIEZO1, inhibition of the bone morphogenetic proteins (BMP)/small mother against decapentaplegic (SMADs) pathway was involved in hepatic iron metabolism impairment (106). In addition, another important factor for iron balance is emojuvelin (HJV), a co-receptor of BMP that is degraded in juvenile hemochromatosis, causing severe hepcidin deficiency and iron overload.…”