Zhou Zijing, Li Jinyuan Vero, Martinac Boris, Cox Charles D
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.
St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Front Pharmacol. 2021 Nov 19;12:766416. doi: 10.3389/fphar.2021.766416. eCollection 2021.
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 -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.
编码机械门控离子通道Piezo1的基因中的错义突变与多种疾病有关。功能获得性变体与遗传性贫血有关，功能丧失性变体与全身性淋巴管发育异常和二叶式主动脉瓣有关。两个先前已鉴定的突变S217L和G2029R，均表现出质膜转运减少。在这里，我们表明这两个突变与野生型Piezo1通道相比，还表现出稳定性降低和更新率更高。这是通过增加泛素化和随后的蛋白酶体降解而发生的。与此一致的是，使用N-乙酰-L-亮氨酰-L-亮氨酰-L-正亮氨酸（ALLN）抑制蛋白酶体减少了两种突变蛋白的降解。虽然ALLN处理不能挽救S217L的功能，但我们通过多种互补方法表明，通过ALLN处理抑制蛋白酶体不仅可以防止G2029R的更新，而且可以增加该变体的膜定位池以及功能性Piezo1机械敏感电流。这些数据与精准医学方法相结合，为治疗Piezo1介导的通道病提供了一条新的潜在治疗途径。
