Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 05 2021
21 05 2021
Historique:
received:
07
04
2020
accepted:
23
03
2021
entrez:
22
5
2021
pubmed:
23
5
2021
medline:
12
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34021134
doi: 10.1038/s41467-021-22782-0
pii: 10.1038/s41467-021-22782-0
pmc: PMC8139980
doi:
Substances chimiques
Gene Products, pol
0
Molecular Chaperones
0
QKI protein, human
0
Qk protein, mouse
0
RNA, Messenger
0
RNA-Binding Proteins
0
SREBF2 protein, human
0
Srebf2 protein, mouse
0
Sterol Regulatory Element Binding Protein 2
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3005Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM130838
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA214800
Pays : United States
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