Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation

Abstract

Missense mutations in the gene that encodes for the mechanically-gated ion channel Piezo1 have been linked to a number of diseases. Gain-of-function variants are linked to a hereditary anaemia and loss-of-function variants have been linked to generalized lymphatic dysplasia and bicuspid aortic valve. Two previously characterized mutations, S217L and G2029R, both exhibit reduced plasma membrane trafficking. Here we show that both mutations also display reduced stability and higher turnover rates than wild-type Piezo1 channels. This occurs through increased ubiquitination and subsequent proteasomal degradation. Congruent with this, proteasome inhibition using N-acetyl-l-leucyl-l-leucyl-l-norleucinal (ALLN) reduced the degradation of both mutant proteins. While ALLN treatment could not rescue the function of S217L we show via multiple complementary methodologies that proteasome inhibition via ALLN treatment can not only prevent G2029R turnover but increase the membrane localized pool of this variant and the functional Piezo1 mechanosensitive currents. This data in combination with a precision medicine approach provides a new potential therapeutic avenue for the treatment of Piezo1 mediated channelopathies.

Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi

“…The localization of GenEPi in plasma membrane and endoplasmic reticulum (ER) reflected that of wild-type Piezo1 while loss-of-function GenEPi-S217L mutant showed ER-retention and affected functionality as previously described in ref. 26 (Supplementary Note 1 and Supplementary Fig. 3 ).…”

Identification of Genetic Risk Factors of Severe COVID-19 Using Extensive Phenotypic Data: A Proof-of-Concept Study in a Cohort of Russian Patients

“…These data suggest that both LZTR1 per se , as target genes affected by rs112544, may be involved in immune system function and anti-viral response. PIEZO1 codes for mechanically-gated ion channels with multiple roles in human organisms, mutations in this gene are comorbid with pathological conditions, namely, hereditary anemia [ 36 ], congenital lymphedema [ 37 ], lymphatic dysplasia [ 38 ], and others, implying that alterations in PIEZO1 may affect the immune response to SARS-CoV-2.…”

The role of mechanically sensitive ion channel Piezo1 in bone remodeling

“…GLD is caused by loss-of-function mutations in the Piezo1 gene ( Martin-Almedina et al, 2018 ), characterized by various symptoms, including non-immune hydrops fetalis (NIHF), lymphedema, and recurrent cellulitis ( Chen Y. et al, 2021 ). Loss-of-function mutations in the Piezo1 gene, especially S217L and G2029R, have been shown to alter protein stability due to increased ubiquitination and subsequent proteasomal degradation ( Zhou et al, 2021 ). Furthermore, Piezo1 loss-of-function compound heterozygous mutations have been reported in patients with Prune Belly Syndrome, which is characterized by a “Prune-like” wrinkled, flaccid ventral abdominal wall with regionally missing or hypoplastic skeletal muscle ( Amado et al, 2024 ).…”