ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
复制标题
果蝇和小鼠的视紫红质生物合成和光感受器存活需要 ER 复合蛋白
DOI：
10.1038/s41418-019-0378-6
复制
发表时间：
2020-02-01
影响因子：
12.4
通讯作者：
Wang, Tao
中科院分区：
文献类型：
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作者：
Xiong, Liangyao;Zhang, Lin;Wang, Tao
视紫红质稳态有缺陷是视网膜变性的主要原因之一，包括色素性疾病。为了鉴定视紫红质生物合成所需的细胞因子，我们在果蝇中为嗜紫红蛋白水平降低的突变体进行了全基因组遗传筛选。我们分离了内质网膜蛋白复合物3（EMC3），EMC5和EMC6中的功能丧失等位基因，它们每个都表现出缺陷的光转传和感光细胞变性。 EMC3，EMC5和EMC6对于独立于ER相关的降解（ERAD）途径的视紫红质合成至关重要，这消除了错误折叠的蛋白质。我们为所有EMC亚基产生了无效突变，并进一步证明了不同的EMC亚基在不同的细胞功能中起着作用。小鼠中EMC3基因的有条件敲除导致视紫红质蛋白的错误定位以及锥形和棒感受器细胞的死亡。这些数据表明EMC亚基在维持视紫红质稳态和感光体功能中的保守作用，并表明视网膜变性也可能是由若云地素早期生物合成的缺陷引起的。
Defective rhodopsin homeostasis is one of the major causes of retinal degeneration, including the disease Retinitis pigmentosa. To identify cellular factors required for the biosynthesis of rhodopsin, we performed a genome-wide genetic screen in Drosophila for mutants with reduced levels of rhodopsin. We isolated loss-of-function alleles in endoplasmic reticulum membrane protein complex 3 (emc3), emc5, and emc6, each of which exhibited defective phototransduction and photoreceptor cell degeneration. EMC3, EMC5, and EMC6 were essential for rhodopsin synthesis independent of the ER associated degradation (ERAD) pathway, which eliminates misfolded proteins. We generated null mutations for all EMC subunits, and further demonstrated that different EMC subunits play roles in different cellular functions. Conditional knockout of the Emc3 gene in mice led to mislocalization of rhodopsin protein and death of cone and rod photoreceptor cells. These data indicate conserved roles for EMC subunits in maintaining rhodopsin homeostasis and photoreceptor function, and suggest that retinal degeneration may also be caused by defects in early biosynthesis of rhodopsin.