Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency.
Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency.
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Qki激活Srebp2介导的胆固醇生物合成，以维持眼睛晶状体的透明度。
DOI：
10.1038/s41467-021-22782-0
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发表时间：
2021-05-21
影响因子：
16.6
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Shin S;Zhou H;He C;Wei Y;Wang Y;Shingu T;Zeng A;Wang S;Zhou X;Li H;Zhang Q;Mo Q;Long J;Lan F;Chen Y;Hu J
眼晶状体细胞中胆固醇生物合成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调节的仍不清楚。在这里，我们表明颤动(Qki)是参与眼睛晶状体中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缺陷小鼠表现出与胆固醇生物合成途径相关的基因下调，导致眼睛晶状体中总胆固醇水平显著降低。晶状体上皮细胞中Qki缺失的小鼠表现出蛋白质聚集体的进行性积累，最终导致白内障。值得注意的是，外用类固醇可以减轻这些缺陷。从机制上讲，我们证明Qki通过在胆固醇生物合成基因的启动子区域招募Srebp2和Pol II来促进胆固醇的生物合成。支持其作为转录共激活因子的功能，我们证明了Qki直接与单链DNA相互作用。总之，我们认为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。眼球晶状体细胞富含维持晶状体透明度的胆固醇，而胆固醇生物合成的中断会导致白内障。作者表明，Qki调控的胆固醇生物合成对于维持晶状体细胞膜的完整性和正确的蛋白质折叠是必不可少的。
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. Eye lens cells are highly enriched in cholesterol that sustains lens transparency, and disruption of cholesterol biosynthesis leads to cataracts. The authors show that cholesterol biosynthesis regulated by Qki is essential for maintenance of membrane integrity of lens cells and proper protein folding.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
饮食和内源性的小分子会影响透镜白内障的发作。
影响因子：
3.4
作者：
Barnes, Stephen;Quinlan, Roy A.
通讯作者：
Quinlan, Roy A.
影响因子：
4.6
作者：
de Bruin RG;van der Veer EP;Prins J;Lee DH;Dane MJ;Zhang H;Roeten MK;Bijkerk R;de Boer HC;Rabelink TJ;van Zonneveld AJ;van Gils JM
通讯作者：
van Gils JM
DOI：
10.1006/faat.1996.0005
发表时间：
1996-01-01
期刊：
FUNDAMENTAL AND APPLIED TOXICOLOGY
影响因子：
--
作者：
Hartman, HA;Myers, LA;Tse, FLS
通讯作者：
Tse, FLS
影响因子：
5.7
作者：
Backe, PH;Messias, AC;Cusack, S
通讯作者：
Cusack, S