Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase
Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase
复制标题
施奈德角膜营养不良相关的 UBIAD1 突变通过稳定 HMG-CoA 还原酶导致角膜胆固醇积累
DOI：
10.1371/journal.pgen.1008289
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发表时间：
2019-07-01
期刊：
影响因子：
4.5
通讯作者：
Luo, Jie
中科院分区：
文献类型：
--
作者：
Jiang, Shi-You;Tang, Jing-Jie;Luo, Jie
Schnyder角膜营养不良是一种罕见的遗传性眼病，其特征是过量游离胆固醇沉积导致角膜混浊。UbiA异戊烯基转移酶结构域蛋白-1（UBIAD 1）是一种催化辅酶Q10和维生素K-2生物合成的酶。已经发现超过20种UBIAD 1突变与人类SCD相关。这些突变体如何促进SCD的发展尚未完全了解。在这里，我们确定HMGCR作为结合伴侣的UBIAD 1使用质谱。与野生型UBIAD 1的高尔基体定位相反，SCD相关突变体主要存在于内质网（ER）中，并与Insig-1竞争HMGCR结合，从而防止HMGCR降解并增加胆固醇生物合成。杂合Ubiad 1 G184 R敲入（Ubiad 1（G184 R/+））小鼠在各种组织中表达升高水平的HMGCR蛋白。老年Ubiad 1（G184 R/+）小鼠表现出角膜浑浊和游离胆固醇积聚，模仿了SCD患者的临床表现。总之，这些结果表明，SCD相关的突变UBIAD 1损害其ER到高尔基体的运输，并增强其与HMGCR的相互作用。UBIAD 1对HMGCR的稳定作用增加了胆固醇的生物合成，最终导致胆固醇在角膜中积聚。
Schnyder corneal dystrophy (SCD) is a rare genetic eye disease characterized by corneal opacification resulted from deposition of excess free cholesterol. UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is an enzyme catalyzing biosynthesis of coenzyme Q10 and vitamin K-2. More than 20 UBIAD1 mutations have been found to associate with human SCD. How these mutants contribute to SCD development is not fully understood. Here, we identified HMGCR as a binding partner of UBIAD1 using mass spectrometry. In contrast to the Golgi localization of wild-type UBIAD1, SCD-associated mutants mainly resided in the endoplasmic reticulum (ER) and competed with Insig-1 for HMGCR binding, thereby preventing HMGCR from degradation and increasing cholesterol biosynthesis. The heterozygous Ubiad1 G184R knock-in (Ubiad1(G184R/+)) mice expressed elevated levels of HMGCR protein in various tissues. The aged Ubiad1(G184R/+) mice exhibited corneal opacification and free cholesterol accumulation, phenocopying clinical manifestations of SCD patients. In summary, these results demonstrate that SCD-associated mutations of UBIAD1 impair its ER-to-Golgi transportation and enhance its interaction with HMGCR. The stabilization of HMGCR by UBIAD1 increases cholesterol biosynthesis and eventually causes cholesterol accumulation in the cornea.