Journal
PLOS GENETICS
Volume 15, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1008289
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Funding
- NNSF of China [31600651, 91753204, 31700711, 31690102, 31701030, 91754102, 31771568]
- MOST of China [2016YFA0500100]
- 111 Project of Ministry of Education of China [B16036]
- Natural Science Foundation of Hubei Province [2016CFA012]
- Shanghai Science and Technology Council [18ZR1411200]
- Shenzhen City Technology Basic Research Program [JCYJ20170818144026198]
- National Key Technology RD Program [2015BAK45B00]
- Wuhan University Interdisciplinary Program [2042017kf0240]
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Schnyder corneal dystrophy (SCD) is a rare genetic eye disease characterized by corneal opacification resulted from deposition of excess free cholesterol. UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is an enzyme catalyzing biosynthesis of coenzyme Q10 and vitamin K-2. More than 20 UBIAD1 mutations have been found to associate with human SCD. How these mutants contribute to SCD development is not fully understood. Here, we identified HMGCR as a binding partner of UBIAD1 using mass spectrometry. In contrast to the Golgi localization of wild-type UBIAD1, SCD-associated mutants mainly resided in the endoplasmic reticulum (ER) and competed with Insig-1 for HMGCR binding, thereby preventing HMGCR from degradation and increasing cholesterol biosynthesis. The heterozygous Ubiad1 G184R knock-in (Ubiad1(G184R/+)) mice expressed elevated levels of HMGCR protein in various tissues. The aged Ubiad1(G184R/+) mice exhibited corneal opacification and free cholesterol accumulation, phenocopying clinical manifestations of SCD patients. In summary, these results demonstrate that SCD-associated mutations of UBIAD1 impair its ER-to-Golgi transportation and enhance its interaction with HMGCR. The stabilization of HMGCR by UBIAD1 increases cholesterol biosynthesis and eventually causes cholesterol accumulation in the cornea.
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