Turner Elizabeth M, Schlieker Christian
Department of Molecular Biophysics & Biochemistry, Yale University , New Haven, CT, USA.
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA; Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA.
Rare Dis. 2016 Sep 27;4(1):e1241363. doi: 10.1080/21675511.2016.1241363. eCollection 2016.
Lamin B Receptor (LBR) is an inner nuclear membrane protein associated with the rare human diseases Pelger-Huët anomaly and Greenberg skeletal dysplasia. A new study has used CRISPR/Cas9-mediated genetic manipulations in a human cell system to determine that the molecular etiology of these previously poorly understood disorders is a defect in cholesterol synthesis due to loss of LBR-associated sterol C14 reductase activity. The study furthermore determined that disease-associated LBR point mutations reduce sterol C14 reductase activity by decreasing the affinity of LBR for the reducing agent NADPH. Moreover, two disease-associated LBR truncation mutants were found to be highly unstable at the protein level and are rapidly turned over by a novel nuclear membrane-based protein quality control pathway. Thus, truncated LBR variants can now be used as model substrates for further investigations of nuclear protein quality control to uncover possible implications for other disease-associated nuclear envelopathies.
核纤层蛋白B受体（LBR）是一种内核膜蛋白，与罕见的人类疾病Pelger-Huët异常和格林伯格骨骼发育不良有关。一项新研究在人类细胞系统中利用CRISPR/Cas9介导的基因操作确定，这些之前了解甚少的疾病的分子病因是由于与LBR相关的固醇C14还原酶活性丧失导致的胆固醇合成缺陷。该研究还确定，与疾病相关的LBR点突变通过降低LBR对还原剂NADPH的亲和力来降低固醇C14还原酶活性。此外，发现两个与疾病相关的LBR截短突变体在蛋白质水平上高度不稳定，并通过一种新的基于核膜的蛋白质质量控制途径迅速被清除。因此，截短的LBR变体现在可作为模型底物，用于进一步研究核蛋白质量控制，以揭示对其他与疾病相关的核膜病可能产生的影响。
