UBIAD1, a Prenyltransferase Enzyme Modulates Biological Functions Required for the Intracellular Homeostasis Maintenance

Literature Review

UBIAD1, a Prenyltransferase Enzyme Modulates Biological Functions Required for the Intracellular Homeostasis Maintenance

Corresponding author:Dr. Samira Zohra MIDOUN , Key Laboratory of Molecular Biophysics, Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China, 430074, Tel: 86-27-87792510; Fax: 86-27-87792170; Email: lhong@mail.hust.edu.cn

Abstract

Ever since a human version of Drosophila heixuedian (heix) has been identified as a tumor suppressor protein, a pertinent literature got deep interest to the human UBIAD1 protein, in terms to further evaluate the occurred molecular mechanism driving its function in human beings. Ubiad1 is a gene ubiquitously expressed in normal human tissues. The protein harbors a prenyltransferase functional domain conserved throughout the evolution. Under specific conditions, UBIAD1 participates in HMGCoA reductase degradation, thus preventing intracellular cholesterol accumulation. Cholesterol aggregation in the cornea is one of the fundamental reasons that causes

SCD (Schnyder Corneal Dystrophy), a genetic disorder associated to defective UBIAD1 function. SCD mutations or loss ofUBIAD1 lead to cancer progression by disrupting the process of UBIAD1/menaquinone-mediated cholesterol regulatory network. Interestingly, UBIAD1-reductase complex formation decides for the sub-localization of this prenyltransferase  enzyme at ER levels or at Golgi membranes (after translocation). The profound effect of human UBIAD1 enzyme not only relies on its ability to synthesize menaquinone-4 (MK-4, vitamin K2) but also in the synthesis of CoQ10 (coenzyme Q10). Vitamin K2 serves as an electron carrier that rescues mitochondrial

dysfunction in Drosophila and prevents mutated Pink-1-assoiated Parkinson’s disease. In addition, this vitamin effectively initiates apoptosis in various types of tumors through a caspase-dependent pathway. In another hand, UBIAD1 is crucial for cardiovascular protection function based on its role in CoQ10 biosynthesis. Taken together, UBIAD1 is a gene with multi-functions that spreads its effect to maintain intracellular homeostasis.

Keywords: Ubiad1; Vitamin K2; Coq10, Tumor; Scd; Parkinson’s Disease; Cholesterol; Cardiovascular Disease; CoQ10; SCD

Abbreviations

AfUbiA: Archaeoglobus Fulgidus;

ApoE: Apolipoprotein E;

ApUbiA: Aeropyrum Pernix Ubia;

Bak: Bcl-2 Antagonist Killer 1;

Bar: Barolo;

Bax: Bcl-2–Associated X Protein;

Bcl-2: B-Cell Lymphoma 2;

BID: BH3 Interacting Domain Death Agonist;

COPII: Coat Protein Complex;

CoQ10: Coenzyme Q10, Ubiquinone 10;

CRAC: Cholesterol Recognition Amino Acid Consensus;

E. coli: Escherichia Coli;

eNOS: Endothelial Nitric Oxide Synthase;

ER: Endoplasmic Reticulum;

ERAD: ER-Associated Degradation;

FARM: First Aspartate-Rich Motif;

FISH: Fluorescence In Situ Hybridization;

GGCX: γ -Glutamyl Carboxylase;

GGOH: Geranylgeraniol;

GGPP: Geranylgeranyl Pyrophosphate;

GPP: Geranyl Diphosphate;

GTP: Guanosine Triphosphate;

Heix: Heixuedian;

HEK293: Human Embryonic Kidney Cells;

HMGCR: 3-Hydroxy-3-Methylglutaryl-Coa Reductase;

IPP: Isoprenyl Pyrophosphate;

JNK: C-Jun N-Terminal Kinases;

K1: vitamin K1;

K2: vitamin K2;

K3: vitamin K3;

Kda: Kilodalton;

Leu65Gln: Leucine65 Glutamine;

MG-63: Human Osteoblast-Like Cells;

MK-4: Menaquinone-4;

PARP: Poly (Adp-Ribose) Polymerase;

PD: Parkinson’s Disease;

PHB: Aromatic P-Hydroxybenzoate;

phospho- ERK: Phospho Extracellular Signal- Regulated Kinases;

Reh: Reddish;

RNS: Reactive Nitric Species;

ROS: Reactive Oxygen Species;

Sar1: Secretion Associated Ras-Superfamily Gene1;

SCCD: Schnyder Crystalline Corneal Dystrophy;

SCD: Schnyder Corneal Dystrophy;

SOAT-1: Sterol O-Acyltransferase;

T24: Human Bladder Carcinoma Cell Line;

TBL2: Transducin (Beta)-Like 2;

TCC: Transitional Cell Carcinoma;

TERE1: Transitional Epithelial Response Gene 1;

TM: Transmembrane Domain;

UBIAD1: Ubia Prenyltransferase Domain Containing 1;

YY1: Yin Yang-1

Introduction

UBIAD1 (a.k.a TERE1, Transitional Epithelium Response gene 1), a tumor-suppressor gene, has been for the first time screened and characterized by its distinct expression level between normal human tissues and transformed Transitional Cell Carcinoma (TCC) [1]. The gene is ubiquitously expressed in various normal human tissues but mainly manifested in the bladder mucosa, where TERE1 was ab initio discovered in, from which comes the occurrence of its appellation as the Transitional Epithelium Response gene 1 (TERE1). TERE1 gene mapped to chromosome 1p36.11-1p36.33 locus [1], was designated as a center of putative tumor suppressor genes for distinct tumor cell populations [2-4]. Published reports have depicted an estimated division of UBIAD1 between Golgi, ER and mitochondria [5-7]. The subcellular localization varies according to the type of cells and might be disturbed in tumor cells. This disruption may dysregulate the adequate function of the protein. UBIAD1 protein has a prenyltransferase activity [8], principally responsible for vitamin K2 and CoQ10 biosynthesis [5, 6]. Interestingly, intracellular homeostasis of both cholesterol and vitamin K relies on the function of apoE, which besides being one of UBIAD1 substrates, is also an important LXR target gene [9, 10]. Besides, UBIAD1 protein has a binding affinity with HMG CoA reductase [11]. Geranylgeraniol can prevent this binding, inducing reductase degradation and consequently an intracellular cholesterol regulation [12]. It is believed that UBIAD1 enzyme and its product K2 are potential regulators of the intracellular elevated cholesterol amount, a common phenotype encountered in distinct cancer cells and in SCD (Schnyder Corneal Dystrophy) cases [8,13].

The molecular genetic mechanisms of UBIAD1

Features of UBIAD1 protein

The human UBIAD1 gene, spanning 22Kb, encodes an intrinsic membrane protein of 338 amino acids with a molecular weight of 36.8 Kda. This protein contains between eight to ten α-helical transmembrane domains [7, 10, 14] and is produced by three possible generated UBIAD1 transcripts (1.5, 3.1 and  3.5 kb), that comprise up to five unique exons [7, 8, 10, 15].Based on TOPCONS software (http://www.topcons.cbr.su.se), UBIAD1 is a nine transmembrane domains protein (Figure 1). The resulting  protein presents an homology and a high identity to Heixuedian (Heix), a Drosophila protein, interfering in growth mechanism during fly development [16]. As previously divulged [17], mutations within the putative Drosophila Heix protein [16], exhibit a series of cellular and developmental defects, including abnormal imaginal disc growth, hemocyte overproliferation, melanotic tumors, and wing irregularities [18, 19]. UBIAD1 is an extremely conserved gene [7,8,15] commonly named UBIAD1 (UbiA prenyltransferase domain containing 1) referring to the prenyltransferase functional domain it harbors within its protein (from residues 58-333) [8] (Figure 1). This domain is involved in cholesterol metabolism [15] and is principally subject to causal missense mutations [7, 8, 15, 20-24].

Figure 1. Topology diagram of predicted secondary structure (2D model) of human UBIAD1 membrane protein. Human UBIAD1gene encodes an intrinsic membrane protein of 338 amino acids. This protein contains nine α-helical transmembrane domains based on TOPCONS software (http://www.topcons.cbr.su.se). Predicted transmembrane helices (orange)cross the lipid bilayer (gray). Residues out of the plasma membrane are nontransmembrane helices (blue). SCD point mutations, including mutation hotspots (N102 and G177) are highlighted in bubbles. S75F is a polymorphism variant (green). The conserved CRAC and FARM motifs as well as oxido-reductase and heme-regulatory motifs are all depicted.

Human UBIAD1 enzyme and both E. coli UbiA, MenA enzymes are assembled in the UbiA family of membrane-embedded prenyltransferases [6,25,26]. The members of this superfamily share similarities in their sequences and are able to catalyze a common biosynthetic pathway reaction required for the generation of ubiquinones and menaquinones that mediate electron transport [27]. E. coli UbiA enzyme cleaves and releases the isoprenyl chain from the isoprenyl pyrophosphate (IPP) and subsequently, prenylates the aromatic phydroxybenzoate (PHB), a precursor of ubiquinone [14, 27]. UbiA homologs structure comprises nine transmembrane α-helices with two conserved motifs NDxDxxxD and DxxxD (referred as first and second aspartate-rich motifs, respectively), (D: Asp, x: any amino acid). The two conserved motifs settle on the cytoplasmic side of the protein, between the C-terminal ends of TM2 and TM6 and the L2–3 and L6–7 loops [14, 27]. Cheng et al. [27] and Huang et al. [14] have elucidated the crystal structure of UbiA members by screening a UbiA homolog from the archaeal thermophile Aeropyrum pernix (ApUbiA) and Archaeoglobus fulgidus (AfUbiA), respectively [14, 27]. Both studies revealed the existence of Mg 2+ and GPP (Geranyl diphosphate) binding-sites within the central cavity of the protein [14, 27]. R22 and K146 residues, inter alia, tend to maintain the protein attached to GGP molecule. During the prenyl transfer, the liberated diphosphate group is stabilized on the prenyl donor via Mg 2+ atom; itself interconnected by the highly conserved aspartate-rich residues N68, D72 (in the first motif) and D198, D202 (in the second motif) [14]. The above finding [14], coordinating with other studies [28-30], describes UbiA enzymes as Mg2+-dependent GPP binding, during the catalytic mechanism in E. coli [28] and other homologs [14, 29, 30]. Interestingly, several humanUBIAD1 mutations, particularly N102, K181, D236 and D240 (Figure 1), respectively  aligned to the conserved residues N68, K146, D198 and D202 on AfUbiA, and lower or totally abolish the prenyltransferasefunction. This discovery assumes a conservation of both of the Mg2+/diphosphate binding site as well as the prenyltransferase mechanism between these two related protein families, despite distant throughout the evolution [14]. Protein homology indicated that tyrosine is the unique universally conserved site in UbiA family (Pfam database) [31]. When mutated, a loss of function results in UbiA enzymes, involving this tyrosine compound in a particular function applicable to all different branches of UbiA superfamily [14]. UBIAD1protein consists of some specific post-translational modification sites: four putative protein kinase C phosphorylation sites at amino acids 18, 41, 239 and 312, six myristylation sites at positions 68, 86, 98, 142, 166 and 167, three putative CK2 phosphorylation sites at positions 103, 120 and 239 in addition to a putative ASN glycosylation site at amino acid 23 [1, 32]. The existence of a Cholesterol Recognition Amino Acid Consensus (CRAC) motif (100- L(VNTY)Y(DFS)K-109) and a First Aspartate-Rich Motif (FARM) (117-DDRTLVD-123) along UBIAD1 protein, are cholesterol and farnesyl recognition sites, respectively [15, 33].

The heme regulatory motif (30-XCPXX-34) and oxido-reductase motif (145-CXXC-148) may entail cellular redox state during the protein activity [15] (Figure 1).

UBIAD1 and protein-protein interactions:

McGarvey and colleagues [9] engaged the interest in protein- protein interaction studies, in order to deeply understand the function of UBIAD1 protein. Apolipoprotein E (apoE, 34Kda) has been the first UBIAD1-co-precipitated protein detected [9]. This binding is confined by hydrophobic interactions (UBIAD1-apoE: L121-V94) and formation of two salt bridges (N118–R39, N236-L50), which contributes in cholesterol efflux from cells [9, 10].

Soon afterward, Fredericks et al. validated TBL2 (49KDa) as UBIAD1-binding partner [34]. In the same year, HMGCR (3-hydroxy-
3-methylglutaryl-CoA reductase) and SOAT-1 (sterol O-acyltransferase) governing cholesterol biosynthesis [35-37] and storage [38, 39], respectively, have been identified as putative UBIAD1-interacting protein [11]. This multi10 interaction complex form a cycle required for the efficiency of enzymes catalyzing some specific reactions inside the cells; vitamin K synthesis and cholesterol metabolism [11, 40, 41]. In fact, intracellular cholesterol level can be regulated by separate expressions of UBIAD1, TBL2 or by the addition of vitamin K derivatives (K1, K2 or K3), in bladder, prostate and renal tumor cells [10, 34, 42]. This point will be discussed further below in the cholesterol part of this review.

Sub-cellular localization of UBIAD1

Several reports have characterized a discrepancy of UBIAD1 sub-cellular localization depending on cell types; distributed in the Endoplasmic Reticulum (ER) in human osteoblast-like MG-63 cells [6], accumulated in the mitochondria of human keratocytes [7] and localized at Golgi membranes of human and zebrafish endothelial cells [5]. UBIAD1 protein was also localized at Golgi membranes in human prostate carcinoma cell lines PC-3 [43]. The latest finding belongs to a study that claims that UBIAD1 primarily accumulates in ER to be then transported to Golgi via a COPII-complex mediated mechanism where it will be abundantly detained [43]. These results were confirmed in both human embryonic kidney cells (HEK293) and human bladder carcinoma cell line T24 [43]. UBIAD1 RPWS (54-57 residues) (Figure 2) is a motif contributing in Golgi retention signal for T24 and HEK293 cells [43] and seems conserved across all eukaryotic species (ranging from Drosophila to humans) (Figure 2) [43]. Moreover, this motif affects the tumor suppressing activity of the protein [43]. The positive charge of Arginine (R) 54 in RPWS motif binds and stabilizes the negatively charged GTP (guanosine triphosphate) of Sar1, a GTPase protein found in COPII vesicles [43]. COPII refers to a Coat Protein complex that transports proteins from ER to Golgi by an anterograde transport;

Figure 2. Multiple sequence alignment of UBIAD1 putative orthologs throughout 18 distinct species (ClustalW alignment and Geneious program). Red arrows mark the mutated residues (SCD disorder) that are identical throughout the 18 species. Black arrows indicate point variants associated to the disease, and that differ in some species. S75F polymorphic site is indicated by a blue arrow. RPWS motif (54-57 amino acids) is an essential Golgi retention signal (orange bar) and LAY motif (71-73 aminoacids) is an important Endoplasmic Reticulum retention signal (pink bar). Both motifs remain conserved among all species (excluding E.coli). Blue bars above the alignment depict positions of the nine predicted transmembrane domains in UBIAD1 structure. Note: The number of human amino acids (homo) in each end of line is marked.

In this case, the interaction between the complex and the motif allows the displacement of UBIAD1 protein from ER to Golgi. Hirota et al. have reported that D112 and K181 alanine mutants were not localized in the Golgi and considered that COPII- complex formation could be interrupted in these mutants [44]. Geranylgeraniol, an alcohol of derivative geranylgeranyl pyrophosphate, can also regulate the subcellular localization of the prenyltransferase enzyme. UBIAD1protein originally localizes to membranes of ER and binds to HMG Co reductase, a cholesterol biosynthetic enzyme when cells are exposed to sterols. However, geranylgeraniol (GGOH) triggers the splitup of wild type UBIAD1-reductase complex and consequently, the delivery of UBIAD1 from ER to Golgi membranes. Interestingly, N102S and G177R variants remain accumulated in ER and associated to the reductase, suggesting the weak affinity of the two mutants for GGPP (resulting by phosphorylation of geranylgeraniol) [12]. We are speculating that both of COPII complex and GGOH might play a pivotal role in the intracellular trafficking mechanism of UBIAD1 (subcellular localization). In the wildtype protein, GGOH is phosphorylated and the resulted GGPP specifically recognizes and binds to UBIAD1. COPII proteins intervene to deliver UBIAD1-GGPP complex from ER to Golgi by allowing the interaction between GTP of Sar1 subunit of COPII complex and arginine 54 (from RPWS motif). When UBIAD1 is affected by SCD-mutations (S102 and R177), the protein conformation changes, and GGPP cannot bind to it. Consequently altered UBIAD1 remain at ER levels even with the presence of COPII proteins, also suggesting that the formation of UBIAD1-GGOH complex is necessary to allow its recognition by COPII proteins and tolerate its transfer to Golgi (Figure 3).

Regulation of human UBIAD1 gene expression

Funahashi et al. have finally clarified that a transcription factor, named YY1 (Yin yang- 1), participates in UBIAD1 gene transcriptional activity [45]. YY-1 is a ubiquitous transcription fac tor belonging to the GLI-Kruppel class of zinc finger proteins [46, 47]. It can repress or activate many genes by binding to sites overlapping the transcription start site of their promoters  [48]. Based on the intensity of luciferase activity on mutant constructs, wild-type UBIAD1 promoter was suggested to be at -590 and +353bp region in both MG-63 and HEK293 cells. Alignment of the humanUBIAD1 promoter fragments showed that the YY1 consensusbinding sequence (5’-CAAGATGGC-3’) is highly conserved between several species and localized near the transcription start site of the promoter [45].

YY-1 function was not only limited to positively regulate UBIAD1 gene expression (via its promoter), but also to affect UBIAD1 conversion activity (MK-4 concentration) [45].

UBIAD1 biosynthetic enzyme activity (Function and Physiology)

Vitamin K2 biosynthesis

In 2010, Nakagawa and collaborators attributed a new function to UBIAD1 as a menaquinone-4 (MK-4, vitamin K2) biosynthetic
enzyme, a predominant form in humans [6]. Vitamin K2 results by way of conversion of dietary phylloquinone (K1) into menadione (K3); an intermediate form prenylated by geranylgeranyl pyrophosphate enzyme (GGPP) and that generates the final component K2 (reaction catalyzed by UBIAD1 protein) [6, 26, 49] (Figure 4). MK-4 is uncoordinatedly distributed in different tissues, preferentially at high concentrations

Figure 3. An assumptive model of the displacement of UBIAD1 protein from the Endoplasmic Reticulum to Golgi apparatus. (A)In wild-type form, UBIAD1 protein first localizes to ER. GGOH is phosphorylated and form GGPH that firmly binds to the protein. At the same instant, GGP, negatively charged and belonging to Sar1 (COPII subunit) assembles to the Arginine (R) 54-based ER localization (RPWS motif of UBIAD1). As a result, UBIAD1 exits from ER membrane to be then transported to Golgi apparatus via COPII traffic mechanism. (B) Mutated UBIAD1 protein is suggested to not be recognized by GGPP and thus, COPII complex might not be able to extract UBIAD1 alone from ER membrane. Mutated UBIAD1 stays localized at ER.

ER: Endoplasmic Reticulum, GGOH: Geranylgeraniol, GGPP: Geranylgeranyl Pyrophosphate, COPII: Coat Protein Complex, GTPp-p-p: Guanosine 5’-Triphosphate, Sar1: Secretion associated ras-superfamily gene1.

Figure 4. The biochemical role of UBIAD1 in the conversion of K vitamins into vitamin K2. Vitamin K2 (K2) belongs to the vitamin K family and is originated from the plant form, phyllaquinone (K1). During the intestinal absorption, the side-chain is removed from phylloquinone and menadione (K3) is formed. K3 is then delivered to tissues through the blood circulation and is subsequently prenylated by UBIAD1 via GGPP and generate MK-4. GGPP: Geranylgeranyl Pyrophosphate.

in the brain, kidney and pancreas [50]. Similarly to UBIAD1 in humans, menA 13 gene participates in the biosynthetic pathway of menaquinones and confers the prenyltransferase function in E. coli [27,51]. Hirota et al. have recently reported that four highly conserved domains (I to IV) along UBIAD1 protein were required during the process of MK-4 biosynthesis [48]. The enzymatic activity was abolished in all UBIAD1 deletion mutants (including SCD mutants: N102S, D112G, R119G, T175I, N232S), pointing the importance of each domain in the correct function of UBIAD1 and to maintain the protein active during MK-4 synthesis. Evidence links K vitamins to several health benefits, for instance: effects in blood coagulation and bone metabolism [6], in corneal health and visual acuity [11]. Moreover, vitamin K2 and K3 are redox-cycling and alkylating Quinones that can generate oxidative stress and lead to growth inhibition in various cancer cells, apoptosis or necrosis [52-56]. These properties were consistent with results reported in colon [57], pancreatic cancer cell lines [58], hepatocellular carcinoma Smmc-7721 cells [59] and RCC cell lines [42]. MK-4 treatment induces cell death in colon cancer cell lines, which respond differently either by autophagy or apoptosis [57]. K1/K2 also initiates apoptosis in some pancreatic cells via a caspase-dependent pathway and activation of BAX, a pro-apoptotic Bcl-2 family member [58]. Likewise, when combined to Sorafenib, K1 lowers phospho-ERK, anti-apoptotic Bcl-2 protein expression and activates the extrinsic apoptotic pathway by up-regulation of caspases 3/8, PARP, JNK and BID, another pro-apoptotic Bcl-2 family member [60]. Smmc-7721 cells are sensitive under the action of vitamin K2, promoting the elevation of caspases 3/8 associated with the activation of P53 protein phosphorylated at serine 20 [59]. In RCC cells, exogenous UBIAD1 increased caspases 3/7 activity [42]. Moreover, Karasawa et al. [61] have postulated that K2-mediated apoptosis in leukemic cells is likely induced by its covalent bond with Bak (Bcl-2 antagonist killer 1) at cystein-166 site [61]. Apart from these activities, vitamin K physiologically acts as a cofactor for γ-glutamyl carboxylase (GGCX) taking part in  the conversion of glutamic acid residues to γ- carboxyglutamicacid residues, during post-translational modifications of various  itamin Kdependent proteins [49, 62]. Of additional interest, UBIAD1-mediated vitamin K2 has been defined as a central modulator of lipid homeostasis via the activation of SXR target genes [34, 42, 49, 63]. K2 exerts a differentiation-promoting effect on myeloid progenitors through a dependent-SXR signaling, and an anti-apoptotic effect on erythroid progenitors through an independent-SXR signaling [64]. These recent studies support the idea that reduced UBIAD1/vitamin K2 level may contribute to different human cancer progression.

CoQ10 biosynthesis and oxidative stress generation

Zebrafish barolo, the xenopus homolog of UBIAD1 is a key enzyme for the prenylation of CoQ10 (coenzyme Q10, Ubiquinone 10) on Golgi membrane [5]. CoQ10, a common form found in zebrafish and humans, is a lipid-soluble antioxidant that plays an important role in protecting biological membranes from oxidative damage, and a regulator of eNOS (endothelial Nitric Oxide  Synthase) activity crucial for redox balance in endothelial cells [5]. Fredericks and co-workers demonstrated that TBL2, TERE1 and K2 influence and enhance the oxidative stress level, relevant with the elevated transmembrane potential detected in the mitochondria [34, 42]. Substantially, ROS/RNS was generated in RCC cells in response to ectopic UBIAD1 expression [42].

Cholesterol

Fredericks et al. associated the castration-resistant prostate cancer-elevated cholesterol phenotype to the repression of SXR target genes [65]. UBIAD1-mediated synthesis of K2 could induce a reversal effect in the phenotype by turning-on SXR target genes (cholesterol hydroxylation, protein efflux, androgen catabolism) [65]. Based on the above study results, cholesterol homeostasis tends to be well-related to MK-4 biosynthesis (Figure 5). In fact, another research has shown a possible linkage  between MK-4 biosynthetic activity of UBIAD1 protein and intracellular cholesterol level [44]. When Hirota et al. created D112, C145 alanine mutants, they could observe a reduced MK-4 synthetic activity and an increase in cholesterol level, suggesting that MK-4 controls cholesterol levels in the cells [44]. The explanation might be as follows: both of cholesterol and MK-4 use FPP as a common substrate for their synthesis; cholesterol synthesis requires GPP and FPP as precursors via the mevalonate pathway [17, 66]. At the same instant, MK-4 biosynthesis is catalyzed by UBIAD1 prenyltransferase with GGPP, itself produced from FPP. According to this idea, when mutant versions of UBIAD1 are produced (in this case, SCD-associated mutants of UBIAD1), MK-4 is synthesized in small amounts and thus, favors FPP to be preferentially consumed as a precursor for cholesterol synthesis more than for GGPP  synthesis, consequently leading to an overproduction of cholesterol[44]. In a same way of interest, Schumacher et al. depicted how the accumulation of cholesterol in SCD patients can be regulated by UBIAD1 and cholesterol biosynthetic enzyme HMG CoA reductase [12]. Under sterol molecules exposure, UBIAD1 firmly binds to HMG CoA reductase, protecting it from its degradation by the proteasome. Thereby, ERAD (ER-associated degradation) of reductase is initiated; Insig proteins get attached to the membrane domain of reductase and consequently allow its ubiquitination by gp78 and Trc8 ligases. In another way, geranylgeraniol tends to disrupt the gathering of UBIAD1-reductase complex, thus enhancing sterol- induced ERAD reaction [67]. SCD-associated UBIAD1 mutants (mainly N102S and G177R) stay attached to the reductase, even with presence of geranylgeraniol and therefore,inhibits ERAD of the enzyme [12].

Interestingly, S102 and R177 variants remain accumulated in ER and still associated to the reductase, suggesting the weak affinity of the two mutants for GGPP (resulting by

Figure 5. General summary of TERE1/UBIAD1 activity and vitamin K2-modulated cellular effects. Vitamin K2 is initially biosynthesized from vitamin K1 (Phylloquinone) that produces the intermediate K3 after an intestinal absorption. The reaction requires a prenylation brought by UBIAD1 enzyme. ApoE binds by affinity to the protein and induces cholesterol and vitamin K transport through the cells. UBIAD1 protein acts via a vitamin K2-independent pathway, that is up to now unclear and a vitamin K2-dependant pathway. In the latter process, UBIAD1 distributes to different compartments (ER, Golgi, Nucleus and Mitochondria),  reates affinities withvarious molecules/enzymes and thus regulates specific intracellular functions. For instance, when the protein binds to HMGCo A reductase enzyme in ER, it will activate consecutive ubiquitination and proteasome degradation of reductase that will regulate cholesterol expression in the cell. In this way, UBIAD1 can translocate to Golgi. K1: vitamin K1, K2: vitamin K2, K3: vitamin K3, VK: K vitamins, TERE1/UBIAD1: prenyltransferase activity, apoE: apolipoprotein E, TBL2: Transducin-Beta-Like 2, HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase, SOAT1: Sterol O-acyltransferase, CoQ10: Coenzyme Q10, SXR: Steroid and Xenobiotic Receptor, LXR: Liver X receptor, ROS: Reactive Oxygen Species, RNS: Reactive Nitrogen Species, ETC: Electron Transport Chain.

phosphorylation of geranylgeraniol) that can continuously keep reductase within ER without its elimination from the cell and might be the reason of the excess of cholesterol in the corneaof patients affected with SCD [12]. We propose that UBIAD1 mutations in combination with cholesterol cell modulation are strongly related to many diseases; they can both trigger tumor progression, mutated UBIAD1 induces cholesterol deposition in the cornea and characterizes SCD disorder. UBIAD1 mutations lead to a dysfunction in cardiovascular development as well as Parkinson’s disease. Both disorders could also be cholesterol accumulation-related.

UBIAD1 expression and associated pathologies
Defective UBIAD1 expression and tumor progression

In United States, Transitional Cell Carcinoma of the bladder (TCC) is the fourth most common cancer in men and will reach 74,690 new cases in 2014 [68]. McGarvey et al. highlighted  UBIAD1 as one of bladder cancer-related genes characterized by its differential expression in the normal and transformed transitional cell epithelium. In fact, UBIAD1 transcript and protein level were expressed in all normal urothelium cells

Figure 6. The impact of UBIAD1/Heix in the occurrence of distinct diseases, in different cellular locations depending on the implicated compartment. Dysfunction of UBIAD1/Heix (and the involvement of vitamin K2) affects a punch of diseases. Drosophila Heix is a modifier of PINK1 gene that occurs in the mitochondria function and induces Parkinson’s disease when mutated. UBIAD1protects the cardiovascular function via CoQ-10 biosynthesis enzyme at Golgi membranes. Mutated UBIAD1 triggers SCD disorder. Wild-type UBIAD1 regulates the Ras/MAPK pathway and activates apoptosis by likely enhancing JNK and P53 expression, preventing then cancerization. Some current therapies are in process in order to cure sort of types of cancers and to delay the aging process caused by the defect of some genes.

but tend to be substantially reduced/lost with the progression of TCC tumor stages [1, 10] and in RCC [42]. The evaluation of cell proliferation upon restoration of UBIAD1 expression revealed a dramatic growth inhibition in two different human bladder TCC cell lines [1] and in renal tumors [42]. Similarly, the expression rate declined in many prostate tumors [32, 65] but didn’t show any apparent concordance with tumor grades [32]. In this case, transfected UBIAD1contributed to down or up-regulate 16 genes by more than 3- fold in prostate tumors. These genes are connected to proliferation control and tumor progression [32]. Similarly to UBIAD1, reduced apoE protein levels were a common feature in RCC and in invasive TCC tumors [9]. Nevertheless, the expression of apoE protein was not discernible in diverse TCC cell lines and in some other tumor cell lines [9]. According to the negative regulation of cellular proliferation (Ras-MAPK signaling) brought by UBIAD1 [69], as well as the inhibitor effect of apoE in mesangial cell growth [70], the physical interaction between molecules might raise the proliferation arrest in bladder cancer cells [9] by suppressing the Ras-MAPK signaling. In fact, MAP kinase (p42/44) phosphorylation significantly decreased in apoE-treated HEK- 293cells [9]. Mutations in UBIAD1 impair apoE binding [8, 10]. Similarly, loss of function of heix in Drosophila induced cell proliferation by enhancing immune-related pathways, such as Ras/MAPK pathway, JAK/STAT pathway, IMD pathway and Toll pathway [69] (Figure 6).

Causal UBIAD1 mutations in the occurrence of Schnyder Corneal Dystrophy (SCD):

UBIAD1 has been linked to numerous diseases, besides its suggested role in cancer [1] (Figure 6). Two groups [8, 15] described that missense variants in UBIAD1 are causal for the occurrence of SCD (Schnyder Corneal Dystrophy), a disorder previously associated to candidate genes mapped to chromosome 1p36, ascertained by linkage analysis within a large Swedish-Finnish pedigree [8, 15, 71, 72]. SCD is a rare autosomal dominant eye disease manifested by a progressive corneal opacification due to a local metabolic dysregulation of cholesterol/ lipid and accompanied by crystal aggregates in some cases [15]. Originally, SCD was known as SCCD (for Schnyder Crystalline Corneal Dystrophy), based on the last feature cited above. The International Committee for the Classification of Corneal Dystrophies (IC3D) [73] renamed the SCCD to elucidate that crystalline deposition is not a prominent attribute to the diagnosis. In fact, only 50% of patients present crystals in their cornea [15]. The severity of the disease is relevant to the age [13] and patients can gradually lose visual acuity [15]. Hypercholesterolemia and genu valgum are diagnosed in some SCD patients [15], and thus with a possible cardiovascular disorder [8]. Differences in clinical manifestations may be due to other unknown genetic and/or environmental factors. Up to now, 24 reported missense mutations, solely in exons 1 and 2 (within the predicted prenyltransferase domain), have been associated with SCD [7, 8, 15, 20-24, 74]: A97T [7], G98S [23], N102S [8, 11, 15, 20, 21, 74], D112N/G [7, 8, 11], D118G [21], R119G [8, 20], L121F/V [20, 21, 75], V122E/G [7], S171P [21, 76], Y174C [22], T175I [8, 21], G177R/E [11, 15, 21], K181R [22], G186R [21], L188H [7], N232S [8], N233H [22], D236E [21], D240N [24] and I245N [74]. p.N102 and p.G177 codons were categorized as hotspot mutations in SCD families among various populations [11, 21] (Figure 1 and 2). It is necessary to mention that all of the above causal mutations take place at amino acid residues, which are highly conserved within vertebrate (mammalian, mouse, chicken) and invertebrate (Drosophila) homologs [7, 8, 11, 15, 76]. The evolutionary conservation and the physical proximities for most of the reported variants are settled either in the aqueous portions of the protein or at sites where transmembrane helices exit the membrane (loops 1-3) [21]. These mutations interfere with the protein function leading to morbific consequences, except for a polymorphic variant, S75F, predicted to be benign [7, 8]  (Figure 1). Long time ago, Gaynor and co-workers have asserted  that SCD corneas were presenting a high level of apoE expression[77]. Thus, as Weiss and collaborators speculated, the cornea cholesterol accumulation results in the imbalance between cholesterol synthesis and cholesterol removal (UBIAD1– ApoE interaction) [15]. Indeed, defective Ubiad1 gene alters its potential mechanism to interact with substrates of binding partners, like ApoE, TBL2, HMGCR, and accordingly, decreases cholesterol removal from the cornea associated with SCD [8, 10, 11, 15, 21]. Consistently, decreased MK-4 synthesis due to SCD mutations within UBIAD1 (especially p.N102S, p.G177E, and p.G177R) could alter the transcription of SXR target genes and causes cholesterol accumulation [11]. Interestingly, substrate docking simulations showed that vitamin K perfectly  fits into the substrate binding cleft of UBIAD1 protein [7].

Thus, the p.G177E mutant protein triggers structural changes by destroying the arrangement of TM helices and eliminating  some bonds between docked substrates (GGPP and menadione) necessary for the maintenance of vitamin K biosynthesis [11].

UBIAD1 and Parkinson’s disease

Similarly to bacterial MenA and humanUBIAD1 homologs, Drosophila Heix produces vitamin K2 via its prenyltransferase domain [6, 25, 51]. Besides, Drosophila Heix acts as a modifier of Pink1 that encodes a mitochondrial kinase, a conserved protein through the evolution [25, 78]. When mutated, this gene is associated with Parkinson’s disease, a neurodegenerative disorder [79], and affects mitochondrial function in Drosophila [78] (Figure 6).

UBIAD1 and cardiovascular function

Two reports [5, 80] explained how UBIAD1 protein was able to regulate endothelial cell survival and ensures vascular homeostasis during cardiovascular tissues development. In fact, ubiad1 mutant exhibited defects in endothelial cell survival  which consequently induced cardiac edema, cranial hemorrhages as well as vascular degeneration [80]. Besides, UBIAD1 could protect the cardiovascular function by CoQ-10 biosynthesis enzyme involvement and eNOS activity modulation [5].

Animal models

Recent reports have been carried on in order to analyze some specific UBIAD1 function performed in different animal models [5, 25, 80, 81].

Drosophila

As cited above, Drosophila UBIAD1/Heix is a modifier of pink1-associated Parkinson’s disease. Due to its mitochondrial electron transport ability, vitamin K2 can rescue Pink1-related mitochondrial morphology/dysfunction in fruit flies facilitating ATP generation [25, 65]. In contrast, CoQ10 does not rescue the heix mutant phenotype [53]. In another hand, Drosophila Heix was also tested on cell proliferation effect. UBIAD1/Heix plays a crucial function in the developmental process of Drosophila hematopoietic system. Loss of Heix function created an unbalance of hemocytes proliferation and Drosophila differenciation as well as activation of pathways related to hemocytes proliferation and immunity (JAK/STAT, Ras/MAPK, Toll and IMD pathways) [69].

Zebrafish

Furthermore, two separate groups [5, 80] have worked on zebrafish in order to observe the cardiovascular development in this animal. Hegarty et al. [80] reviewed that loss of ubiad1 function exhibits significant reduced cranial blood vessels and an elevation of endothelial cell death in zebrafish reddish/ reh (ubiad1) mutant (Leu65Gln substitution). Mutants also developed a cardiac edema, leading to a myocardial dysfunction [80]. Besides, UBIAD1 was required to generate MK-4 and led to rescue reh endothelial cell apoptosis phenotype [80], in agreement with Drosophila ubiad1 mutant heixuedian (heix) data [25]. However, inhibiting the conversion of K vitamin derivatives did not display any cardiac dysfunction phenotype in zebrafish reh mutants [80]. It is worth mentioning at this point that UBIAD1 may regulate the myocardial function via a vitamin K2-independent pathway, which implies another dimension to UBIAD1 protein activity beyond its ability to synthesize the K vitamin [80].

As for Mugoni and co-workers [5], they speculated that Ubiad1 is a critical factor essential in CoQ10-dependent cardiovascular  oxidative stress protection. In fact, loss of this gene implicated a gradual cardiovascular failure in barolo (bar) mutant by disrupting eNOS-mediated NO production, accumulating oxidative damage and causing a cell death in heart and blood vessels.

Mice

In a further development, Nakagawa and colleagues [81] have explored, in vivo, the UBIAD1 function by using Ubiad1-deficient  (Ubiad1-/-) mouse embryos (mouse Ubiad1, being the homolog of humanUBIAD1 [81]. Ubiad1-/- embryos were lethal at stages beyond E7,5 and presented a premature gastrulation arrest [81]. The Ubiad1-/- embryonic lethal phenotype has been slightly extended but failed to be completely rescued, when Ubiad1+/- pregnant mice were treated by either MK-4 or CoQ10. When measured on Ubiad1+/+ and Ubiad1+/- embryonic stem (ES) and mouse embryonic fibroblasts (MEF) cells, UBIAD1 deficiency has been corroborated to principally affect MK-4 biosynthesis (significantly reduced in Ubiad1+/- cells compared to that of Ubiad1+/+ cells), but not CoQ10 and CoQ9 (prevalent in mice and rats) [81]. In fact, similar expressed CoQ was determined in both genotypes and both cells (cells cited above) [81]. Interestingly, given that both of MK-4 and CoQ10 have an anti-oxidative effect and function as electron carriers in cells, CoQ10 treatment may have partially served to compensate the roles of anti22 oxidation and electron transport of MK-4, which was completely abolished in Ubiad1-/- mice [81]. Once again, this research links UBIAD1 expression to cholesterol metabolism in mice, previously argued in human SCD patients [8, 11]. Collecting these results altogether, MK-4 biosynthesis relies on the accurate expression of UBIAD1, required in the embryonic development of mice [81].

Conclusions

The evidence for UBIAD1 and vitamin K2 as good candidates is potentially promising in the therapy of disorders associated to cholesterol accumulation (SCD and cardiovascular disease). The subcellular localization disturbed in tumor cells might be studied so that it can enlighten the vision concerning the adequate function of the protein and its affinities with specific substrates. Regarding molecular mechanisms of UBIAD1/vitamin K2-induced apoptosis in cancer cells, details are yet to be finalized but the project is nowadays in progress. Hence, given that a treatment with K vitamins, in this case vitamin K2, induces the expression of some specific proteins involved in cell death, may be used in antitumor therapies to cure some types of cancers as well as in cholesterol-related diseases.

Acknowledgments

I am grateful to my professor Dr. Ling Hong who has continuously supported me all along the redaction of the literature review. A special thanks to the China Scholarship Council (CSC) for my Doctoral stipends.

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