Role of UBIAD1 in Intracellular Cholesterol Metabolism and Vascular Cell Calcification

Li, Sha; Wei, Guo; Han, Xue; Dai, Wanwei; Diao, Zongli; Liu, Wenhu

doi:10.1371/journal.pone.0149639

Cited by 12 publications

(11 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…UBIAD1 inhibits post-ubiquitination steps in ERAD of reductase (12), the molecular basis of which is currently under investigation. In contrast to our findings summarized above, previous studies reported reduced levels of cholesterol not only in cells overexpressing wild-type, full-length UBIAD1, but also in those expressing truncated and SCD-associated variants (including N102S) of UBIAD1 (22)(23)(24). In addition, a mild accumulation of intracellular cholesterol was observed upon RNAi-mediated knockdown of UBIAD1.…”

Section: Ubiad1 Coordinates Sterol and Nonsterol Isoprenoid Synthesiscontrasting

confidence: 99%

UbiA prenyltransferase domain–containing protein-1 modulates HMG-CoA reductase degradation to coordinate synthesis of sterol and nonsterol isoprenoids

Schumacher

Jun

Johnson

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

UBIAD1 (UbiA prenyltransferase domain-containing protein-1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K We previously reported that sterols stimulate binding of UBIAD1 to endoplasmic reticulum (ER)-localized 3-hydroxy-3-methylglutaryl (HMG) CoA reductase. UBIAD1 binding inhibits sterol-accelerated, ER-associated degradation (ERAD) of reductase, one of several mechanisms for feedback control of this rate-limiting enzyme in the branched pathway that produces cholesterol and nonsterol isoprenoids such as GGpp. Accumulation of GGpp in ER membranes triggers release of UBIAD1 from reductase, permitting its maximal ERAD and ER-to-Golgi transport of UBIAD1. Mutant UBIAD1 variants associated with Schnyder corneal dystrophy (SCD), a human disorder characterized by corneal accumulation of cholesterol, resist GGpp-induced release from reductase and remain sequestered in the ER to block reductase ERAD. Using lines of genetically manipulated cells, we now examine consequences of UBIAD1 deficiency and SCD-associated UBIAD1 on reductase ERAD and cholesterol synthesis. Our results indicated that reductase becomes destabilized in the absence of UBIAD1, resulting in reduced cholesterol synthesis and intracellular accumulation. In contrast, an SCD-associated UBIAD1 variant inhibited reductase ERAD, thereby stabilizing the enzyme and contributing to enhanced synthesis and intracellular accumulation of cholesterol. Finally, we present evidence that GGpp-regulated, ER-to-Golgi transport enables UBIAD1 to modulate reductase ERAD such that synthesis of nonsterol isoprenoids is maintained in sterol-replete cells. These findings further establish UBIAD1 as a central player in the reductase ERAD pathway and regulation of isoprenoid synthesis. They also indicate that UBIAD1-mediated inhibition of reductase ERAD underlies cholesterol accumulation associated with SCD.

show abstract

Section: Ubiad1 Coordinates Sterol and Nonsterol Isoprenoid Synthesiscontrasting

confidence: 99%

UbiA prenyltransferase domain–containing protein-1 modulates HMG-CoA reductase degradation to coordinate synthesis of sterol and nonsterol isoprenoids

Schumacher

Jun

Johnson

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…4B). This finding agrees with a recent paper by Liu et al [45] describing that knock-down of UBIAD1, a nonmitochondrial prenyltransferase that synthesizes CoQ in the Golgi, induces an increase in intracellular cholesterol amount. Moreover, Suárez-Rivero et al [46] reported that in fibroblasts from familial hypercholesterolemia patients, the mevalonate pathway was dysregulated, resulting in increased cholesterol levels and CoQ deficiency.…”

Section: Discussionsupporting

confidence: 93%

“…This finding agrees with a recent paper by Liu et al . [45] describing that knock‐down of UBIAD1, a nonmitochondrial prenyltransferase that synthesizes CoQ in the Golgi, induces an increase in intracellular cholesterol amount. Moreover, Suárez‐Rivero et al .…”

Section: Discussionmentioning

confidence: 99%

Coenzyme Q biosynthesis inhibition induces HIF‐1α stabilization and metabolic switch toward glycolysis

et al. 2020

View full text Add to dashboard Cite

The inhibition of coq2 by 4‐nitrobenzoate decreases the CoQ content, promoting the biosynthesis of cholesterol. The increased cholesterol content reduces the plasma membrane fluidity, lowering intracellular oxygen tension. The OxPhos activity and the antioxidant defences are decreased. These conditions favor the stabilization of hypoxia‐inducible factor 1α, which mediates the adaptive metabolic response stimulating the glycolytic pathway, with enhanced glucose entry and induction of the PMOR system to lessening the intracellular reducing power.

show abstract

“…These encompass (i) synthesis of human endogenous form of vitamin K 2 (MK-4) from derivates of a plant form vitamin K 1 [ 10 , 20 – 25 ], (ii) prevention of oxidative damage in tissues by synthesis of non-mitochondrial coenzyme Q10 [ 26 , 27 ], and (iii) direct and indirect interaction with proteins that regulate cholesterol synthesis and transport (HMGCR, SOAT1, apoE) [ 10 , 28 , 29 ]. UBIAD1 protein plays a crucial role in maintaining lipid-cholesterol homeostasis in different cell types [ 10 , 12 , 21 , 30 , 31 ] but the molecular mechanism by which UBIAD1 pathogenic variants affect the cornea leading to lipid deposition in SCD patients has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Clinical diversity in patients with Schnyder corneal dystrophy—a novel and known UBIAD1 pathogenic variants

Sarosiak

Udziela

Ścieżyńska

et al. 2018

Graefes Arch Clin Exp Ophthalmol

View full text Add to dashboard Cite

PurposeSchnyder corneal dystrophy (SCD) is a rare inherited disease that leads to gradual vision loss by the deposition of lipids in the corneal stroma. The aim of this study is to report a novel pathogenic variant in the UBIAD1 gene and present clinical and molecular findings in Polish patients with SCD.MethodsIndividuals (n = 37) originating from four Polish SCD families were subjected for a complete ophthalmological check-up and genetic testing. Corneal changes were visualized by slit-lamp examination, anterior segment optical coherent tomography (AS-OCT), and in vivo confocal microscopy (IVCM).ResultsIn a proband with primarily mild SCD that progressed rapidly at the end of the fifth decade of life, a novel missense pathogenic variant in UBIAD1 (p.Thr120Arg) was identified. The other studied SCD family represents the second family reported worldwide with the UBIAD1 p.Asp112Asn variant. SCD in the remaining two families resulted from a frequently identified p.Asn102Ser pathogenic variant. All affected subjects presented a crystalline form of SCD. The severity of corneal changes was age-dependent, and their morphology and localization are described in detail.ConclusionThe novel p.Thr120Arg is the fourth SCD-causing variant lying within the FARM motif of the UBIAD1 protein, which underlines a high importance of this motif for SCD pathogenesis. The current study provides independent evidence for the pathogenic potential of UBIAD1 p.Asp112Asn and new information useful for clinicians.

show abstract

Role of UBIAD1 in Intracellular Cholesterol Metabolism and Vascular Cell Calcification

Cited by 12 publications

References 36 publications

UbiA prenyltransferase domain–containing protein-1 modulates HMG-CoA reductase degradation to coordinate synthesis of sterol and nonsterol isoprenoids

UbiA prenyltransferase domain–containing protein-1 modulates HMG-CoA reductase degradation to coordinate synthesis of sterol and nonsterol isoprenoids

Coenzyme Q biosynthesis inhibition induces HIF‐1α stabilization and metabolic switch toward glycolysis

Clinical diversity in patients with Schnyder corneal dystrophy—a novel and known UBIAD1 pathogenic variants

Contact Info

Product

Resources

About