Abstract
Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.
Highlights
SCD (Schnyder corneal dystrophy) is a rare autosomal dominant eye disease that is characterized by bilateral opacification of the cornea (Klintworth, 2009; Weiss, 2009)
Results of the current experiments form the basis for the model shown in Figure 9 that depicts the role of UBIAD1 in sterol-accelerated ERAD of reductase
As previously proposed (Morris et al, 2014), the reaction is initiated by accumulation of sterols, which triggers binding of Insigs to reductase and results in its gp78/Trc8-mediated ubiquitination (Song et al, 2005; Jo et al, 2011)
Summary
SCD (Schnyder corneal dystrophy) is a rare autosomal dominant eye disease that is characterized by bilateral opacification of the cornea (Klintworth, 2009; Weiss, 2009). Thereafter, opacification of the cornea progresses slowly and leads to reduced visual acuity, which is postulated to be caused by light scattering (Weiss, 2009). The significance of this visual impairment is highlighted by the frequency in which corneal transplant surgery is utilized in treatment of SCD; approximately 50% of SCD patients ≥50 years of age undergo corneal transplant surgery for restoration of normal vision acuity (Weiss, 2007). Systemic dyslipidemia has been reported to be associated with some, but not all cases of SCD (Thiel et al, 1977; Brownstein et al, 1991; Crispin, 2002)
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