Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency

Seula Shin, Hao Zhou, Chenxi He, Yanjun Wei, Yunfei Wang, Takashi Shingu, Ailiang Zeng, Shaobo Wang, Xin Zhou, Hongtao Li, Qiang Zhang, Qinling Mo, Jiafu Long, Fei Lan, Yiwen Chen and Jian Hu ()
Additional contact information
Seula Shin: The University of Texas MD Anderson Cancer Center
Hao Zhou: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University
Chenxi He: Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University
Yanjun Wei: The University of Texas MD Anderson Cancer Center
Yunfei Wang: H. Lee Moffitt Cancer Center & Research Institute
Takashi Shingu: The University of Texas MD Anderson Cancer Center
Ailiang Zeng: The University of Texas MD Anderson Cancer Center
Shaobo Wang: Shandong University
Xin Zhou: Cancer Research Institute of Jilin University, The First Hospital of Jilin University
Hongtao Li: Shanghai Jiaotong University
Qiang Zhang: The University of Texas MD Anderson Cancer Center
Qinling Mo: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University
Jiafu Long: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University
Fei Lan: Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University
Yiwen Chen: The University of Texas MD Anderson Cancer Center
Jian Hu: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22782-0

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