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

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.

Automated summary

Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts. Qki is essential for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens, maintaining the cholesterol level that protects lens from cataract development. Qki regulates cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes, and its depletion leads to protein aggregation and cataract formation in mice.