The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase

Schumacher, Marc; Elsabrouty, Rania; Seemann, Joachim; Jo, Youngah; DeBose‐Boyd, Russell A.

doi:10.7554/elife.05560

Cited by 76 publications

(95 citation statements)

References 64 publications

(105 reference statements)

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“…In the course of our studies, we discovered that GGpp also stimulates translocation of UBIAD1 from the ER to the Golgi (12). SCD-associated UBIAD1 (N102S) and (G177R) are refractory to this GGpp-induced Golgi transport and localize to the ER.…”

Section: Cell Culturementioning

confidence: 97%

“…We postulate that GGOH becomes converted to GGpp, which augments reductase ERAD by enhancing its membrane extraction (21). Recently, we found that sterols also cause reductase to bind to UBIAD1 (12). GGpp triggers release of UBIAD1 from reductase, allowing for its maximal ERAD.…”

Section: Cell Culturementioning

confidence: 99%

“…GGpp triggers release of UBIAD1 from reductase, allowing for its maximal ERAD. Importantly, the addition to cells of farnesol, the alcohol derivative of Fpp, neither inhibits the binding of UBIAD1 to reductase nor augments ERAD of reductase (12,16). Two of the 20 SCD-associated mutants of UBIAD1 (N102S and G177R) resisted GGpp-induced displacement from reductase and thereby blocked its degradation (12).…”

Section: Cell Culturementioning

confidence: 99%

“…The expression plasmids, pCMV-Myc-UBIAD1, which encodes human UBIAD1 containing a single copy of a Myc epitope at the N-terminus under transcriptional control of the cytomegalovirus (CMV) promoter, pCMV-Myc-UBIAD1 (N102S) encoding Myctagged human UBIAD1 harboring the SCD-associated asparagine-102 to serine (N102S) mutation, and pCMV-Myc-UBIAD1 (G177R) encoding Myc-tagged human UIBAD1 harboring the SCD-associated glycine-177 to arginine mutation were previously described (12). The remaining SCD-associated mutants of UBIAD1 were generated using the QuikChange® site-directed mutagenesis kit (Agilent Technologies, Santa Clara, CA) and pCMV-Myc-UBIAD1 as a template.…”

Section: Expression Plasmidsmentioning

confidence: 99%

“…Transient transfection of cells with FuGENE6 transfection reagent was carried out as previously described (12,15). Conditions of subsequent incubations are described in the figure legends.…”

Section: Transfection and Immunofluorescencementioning

confidence: 99%

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Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgUbiA prenyltransferase domain-containing protein-1 (UBIAD1) belongs to the UbiA superfamily of integral membrane prenyltransferases (1). These enzymes contain 8-10 transmembrane helices and catalyze transfer of isoprenyl groups to aromatic acceptors, producing a wide range of molecules such as ubiquinones, hemes, chlorophylls, vitamin E, and vitamin K. In animals, UBIAD1 catalyzes transfer of the 20-carbon geranylgeranyl moiety from geranylgeranyl pyrophosphate (GGpp) to menadione released from plant-derived phylloquinone, thereby generating the vitamin K 2 subtype, menaquinone-4 (MK-4) (2, 3).Mutations in the UBIAD1 gene are associated with Schnyder corneal dystrophy (SCD), an autosomal dominant human eye disease characterized by progressive opacification of the cornea, owing to abnormal accumulation of cholesterol and other lipids (4,5). Systemic dyslipidemia appears to be associated with some, but not all, SCD cases (6, 7). Missense mutations that alter 20 amino acid residues in UBIAD1 have been identified in 50 SCD families (8, 9). Several of these altered amino acids reside within the active site of UBIAD1 (10, 11). A link between UBIAD1 and cholesterol metabolism was first provided by coimmunoprecipitation studies that showed an association of UBIAD1 with the cholesterol biosynthetic enzyme, HMGCoA reductase (8). More recently, we showed that UBIAD1 inhibits sterol-accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of reductase (12), one of several feedback mechanisms that converge on the enzyme to maintain cholesterol homeostasis (13).Abstract UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K 2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1.

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Section: Cell Culturementioning

confidence: 97%

Section: Cell Culturementioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Expression Plasmidsmentioning

confidence: 99%

Section: Transfection and Immunofluorescencementioning

confidence: 99%

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Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome

Foley

Zou

Dunford

et al. 2020

Annals of Neurology

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Objective A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. Methods We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock‐in mouse were done. Results A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient‐derived myogenic cells, and a knock‐in mouse of one of the mutations (Y259C) resulted in prenatal lethality. Interpretation The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332–347.

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Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis

et al. 2021

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KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY‐I. By disrupting the interaction of SQS with cardiac ER‐membrane protein TMEM43, KY02111 impairs TGFβ signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFβ signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFβ/SMAD signaling.

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The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase

Cited by 76 publications

References 64 publications

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome

Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis

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