Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Biology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
Nat Commun. 2021 May 21;12(1):3005. doi: 10.1038/s41467-021-22782-0.
Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; however, how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. Here, we show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. At the transcriptome level, lens-specific Qki-deficient mice present downregulation of genes associated with the cholesterol biosynthesis pathway, resulting in a significant reduction of total cholesterol level in the eye lens. Mice with Qki depletion in lens epithelium display progressive accumulation of protein aggregates, eventually leading to cataracts. Notably, these defects are attenuated by topical sterol administration. Mechanistically, we demonstrate that Qki enhances cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes. Supporting its function as a transcription co-activator, we show that Qki directly interacts with single-stranded DNA. In conclusion, we propose that Qki-Srebp2-mediated cholesterol biosynthesis is essential for maintaining the cholesterol level that protects lens from cataract development.
眼晶状体细胞中胆固醇生物合成的缺陷通常与白内障有关；然而，参与胆固醇生物合成的基因在晶状体细胞中是如何被调控的仍不清楚。在这里，我们表明 Quaking (Qki) 是眼晶状体中参与胆固醇生物合成的基因转录激活所必需的。在转录组水平上，晶状体特异性 Qki 缺陷型小鼠中与胆固醇生物合成途径相关的基因下调，导致眼晶状体中总胆固醇水平显著降低。在晶状体上皮细胞中 Qki 耗竭的小鼠中会出现蛋白聚集体的进行性积累，最终导致白内障。值得注意的是，这些缺陷可以通过局部固醇给药来减轻。在机制上，我们证明 Qki 通过在胆固醇生物合成基因的启动子区域募集 Srebp2 和 Pol II 来增强胆固醇生物合成。支持其作为转录共激活因子的功能，我们表明 Qki 直接与单链 DNA 相互作用。总之，我们提出 Qki-Srebp2 介导的胆固醇生物合成对于维持保护晶状体免受白内障发展的胆固醇水平是必不可少的。
