ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine.
ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine.
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ER相关的囊肿性发病机理和精密医学前景中的降解。
DOI：
10.1172/jci169551
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发表时间：
2023-10-02
影响因子：
15.9
通讯作者：
Li, Ming
中科院分区：
文献类型：
--
作者：
Venkatarangan, Varsha;Zhang, Weichao;Yang, Xi;Thoene, Jess;Hahn, Si Houn;Li, Ming
胱氨酸沉着症是一种溶酶体贮积病，其特征在于二肽胱氨酸在管腔内的积聚。它是由胱氨酸输出体胱氨酸蛋白酶突变引起的。大多数临床报道的突变是由于转运蛋白功能的丧失。在这项研究中，我们鉴定了一种快速降解的疾病变体，称为半胱氨酸蛋白酶（7Δ）。我们证明了这种突变体保留在ER中，并通过ER相关降解（ERAD）途径降解。利用遗传和化学抑制方法，我们阐明了HRD 1、p97、EDEMs和蛋白酶体复合物在胱抑素（7Δ）降解途径中的作用。在了解了降解机制之后，我们测试了先前用于处理CFTR F508Δ的一些化学分子伴侣，并证明它们可以促进半胱氨酸蛋白酶（7Δ）的折叠和运输。引人注目的是，化学伴侣治疗可以降低腔内胱氨酸水平约70%。我们相信，我们的研究最终建立了ERAD和胱氨酸病发病机制之间的联系，并证明了使用化学伴侣治疗胱氨酸蛋白酶（7Δ）的可能性。
Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).