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. 2022 Dec;14(12):a041253. doi: 10.1101/cshperspect.a041253

Post-Translational Regulation of HMG CoA Reductase

Youngah Jo 1, Russell A DeBose-Boyd 1
PMCID: PMC9732902  PMID: 35940903

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an endoplasmic reticulum (ER)-localized integral membrane protein that catalyzes the rate-limiting step in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). HMGCR is subjected to strict feedback control through multiple mechanisms to ensure cells constantly produce essential nonsterol isoprenoids, but do not overaccumulate cholesterol. Here, we focus on the mechanism of feedback control of HMGCR that involves its sterol-induced ubiquitination and ER-associated degradation (ERAD) that is augmented by GGpp. We will also discuss the how GGpp-regulated intracellular trafficking of the vitamin K2 synthetic enzyme UbiA prenyltransferase domain-containing protein-1 (UBIAD1) inhibits HMGCR ERAD to balance the synthesis of sterol and nonsterol isoprenoids. Finally, we will summarize various mouse models, the characterization of which establish that sterol-accelerated, UBIAD1-modulated ERAD plays a major role in regulation of HMGCR and cholesterol metabolism in vivo.

Cholesterol is an essential molecule required for normal function at both the cellular and organismic level. It plays a well-recognized role in animal cells by modulating the integrity and fluidity of membranes and serves as a precursor of bile acids, steroid hormones, and vitamin D (Edwards and Ericsson 1999). In addition, cholesterol participates in cell signaling events; it is covalently attached to the morphogen Hedgehog that modulates several processes required for embryonic development in vertebrate and invertebrate animals (Hu and Song 2019; Qi and Li 2020). A complex biosynthetic pathway has been elucidated in which more than 20 enzymes convert the two-carbon precursor acetate to the tetracyclic, 27-carbon cholesterol molecule (Fig. 1; Bloch 1965). Early studies established that synthesis of cholesterol is subjected to feedback control (Schoenheimer and Breusch 1933; Gould et al. 1953). Subsequently, it was revealed that the two-step reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate was the rate-limiting step in cholesterol synthesis and the site for feedback regulation of the reaction (Bucher et al. 1959, 1960; Gould and Swyryd 1966; Siperstein and Fagan 1966; Siperstein and Guest 1966; Linn 1967). These findings focused considerable attention on the understanding of mechanisms underlying the regulation of HMG CoA reductase (HMGCR), an endoplasmic reticulum (ER)-localized integral membrane protein that catalyzes synthesis of mevalonate.

Figure 1.

Figure 1.

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The mevalonate pathway in animal cells.

In addition to cholesterol and other sterols, the cholesterol synthetic pathway provides a variety of nonsterol isoprenoids including farnesyl pyrophosphate (Fpp), geranylgeranyl pyrophosphate (GGpp), ubiquinone-10, heme, dolichol, and the vitamin K2 subtype menaquinone-4 (MK-4). These nonsterol products of mevalonate metabolism are indispensable for cell viability as they play key roles in processes ranging from protein prenylation (Fpp and GGpp) and glycosylation (dolichol) to cell respiration (ubiquinone-10 and heme) and γ-glutamyl carboxylation (MK-4). Cells must constantly produce nonsterol isoprenoids; however, the overaccumulation of cholesterol and other sterols must be avoided. This is achieved through a multivalent feedback system that operates through transcriptional, translational, and post-translational mechanisms to tightly control the levels of HMGCR (Brown and Goldstein 1980). In this review, we summarize the current understanding of the post-translational control of HMGCR involving its sterol-induced ubiquitination and ER-associated degradation (ERAD) from membranes.

Insig-MEDIATED, STEROL-ACCELERATED UBIQUITINATION AND ERAD OF HMGCR

The cDNA for HMGCR encodes an 887-amino acid protein that can be divided into two distinct domains (Fig. 2A; Chin et al. 1984). The amino-terminal domain contains 349 amino acids and is highly hydrophobic, including eight membrane-spanning helices that anchor the protein to ER membranes (Roitelman et al. 1992). The 548-amino acid carboxy-terminal domain is hydrophilic and projects into the cytosol where it exerts all catalytic activity (Gil et al. 1985; Liscum et al. 1985). When cells are depleted of cholesterol and other sterols, HMGCR is slowly degraded with a half-life of >12 h. This results in production of mevalonate that becomes incorporated into sterol and nonsterol end products. When sterols and other isoprenoids accumulate in membranes, the ERAD of HMGCR is accelerated and its half-life is reduced by >20-fold. Accelerated ERAD of HMGCR is mediated entirely by its membrane domain. This was first indicated by the finding that the soluble catalytic domain rescued cholesterol synthesis in HMGCR-deficient cells and exhibited a long half-life (>10 h) that was not reduced in the presence of sterols (Gil et al. 1985). Studies subsequently showed that sterols accelerated ERAD of a fusion protein in which the catalytic domain of HMGCR was replaced by soluble β-galactosidase (Skalnik et al. 1988). Finally, we showed that the membrane domain of HMGCR undergoes sterol-accelerated ERAD in the absence of the catalytic domain (Sever et al. 2003a). Inhibitors of the 26S proteasome block ERAD of HMGCR, causing accumulation of the ubiquitinated enzyme (Inoue et al. 1991; Ravid et al. 2000). Thus, the membrane domain of HMGCR is both necessary and sufficient for sterol-induced ubiquitination and proteasome-mediated ERAD.

Figure 2.

Figure 2.

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Domain structure of mammalian 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). (A) HMGCR is comprised of a hydrophobic amino-terminal domain with eight membrane-spanning helices required for sterol-accelerated endoplasmic reticulum–associated degradation (ERAD), followed by a hydrophilic catalytic domain that projects into the cytosol. (B) Amino acid sequence and topology of hamster HMGCR. Lysines 89 and 248, which are required for sterol-induced ubiquitination, are highlighted in red.

A key breakthrough in the understanding of HMGCR ERAD was provided by the discovery that sterols cause HMGCR to bind to membrane proteins called Insig-1 and Insig-2 (Sever et al. 2003a,b). Prior to this discovery, Insigs were recognized for their role in cholesterol-mediated regulation of the escort protein Scap (Yang et al. 2002). Scap contains a hydrophobic amino-terminal domain with eight transmembrane helices and a cytosolic carboxy-terminal domain that binds to membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) (Sakai et al. 1997, 1998; Nohturfft et al. 1998). In cholesterol-deprived cells, Scap escorts SREBPs from the ER to Golgi where SREBPs are proteolytically activated (Brown et al. 2018). This activation leads to enhanced expression of genes encoding enzymes in the cholesterol biosynthetic pathway (including HMGCR) and the low-density lipoprotein (LDL) receptor. Sterols cause Insigs to bind a region within the Scap membrane domain that encompasses transmembrane (TM) helices 2–6. This region in Scap, which has become known as the sterol-sensing domain (SSD) (Wu et al. 2022), is similar to TMs 2–6 of HMGCR. Overexpression of the Scap SSD prevented sterol-accelerated ERAD of HMGCR, which prompted us to asses a role for Insigs in the reaction (Sever et al. 2003a). We found that sterols caused Insigs to bind the membrane domain of HMGCR, and this binding was blocked by introduction of mutations in the HMGCR SSD that prevent binding of Scap to Insigs (Sever et al. 2003b). Insig-binding bridges HMGCR to at least three membrane-bound E3 ubiquitin ligases (Song et al. 2005a; Jo et al. 2011; Jiang et al. 2018) that facilitate ubiquitination of cytosolically opposed lysines-89 and -248 in the membrane domain of HMGCR (Sever et al. 2003b). Mutation of these lysine residues to arginine (K89R/K248R) ablate sterol-induced ubiquitination and ERAD of HMGCR (Fig. 2B). HMGCR ubiquitination was also inhibited by SSD mutations that prevent binding to Insigs, supporting the notion that sterol-induced ubiquitination is an obligatory reaction for ERAD.

Potent competitive inhibitors of HMGCR called statins deplete cells of both sterol and nonsterol isoprenoids, triggering the marked accumulation of HMGCR in ER membranes of cells (Endo et al. 1976; Brown et al. 1978). Although the addition of sterols to statin-treated cells triggers ubiquitination of HMGCR, the protein is not completely degraded. Maximal ERAD requires the further addition to cells of nonsterol products of mevalonate metabolism (Nakanishi et al. 1988; Roitelman and Simoni 1992; Correll and Edwards 1994). Our studies disclosed that geranylgeraniol (GGOH), the alcohol derivative of GGpp, augments sterol-accelerated ERAD of HMGCR at a postubiquitination step in the reaction (Sever et al. 2003b). We have identified two postubiquitination steps in the HMGCR ERAD pathway (Hartman et al. 2010; Morris et al. 2014). In the first step, ubiquitinated HMGCR is extracted across ER membranes through the action of valosin-containing protein (VCP)/p97, a member of the hexameric ATPases associated with diverse cellular activities (AAA) superfamily of ATPases that associates with polyubiquitin-binding cofactors Npl4 and Ufd1 (Bodnar and Rapoport 2017a,b; Bodnar et al. 2018). Biochemical evidence indicates that GGOH enhances VCP/p97-mediated extraction of ubiquitinated reductase across ER membranes (Elsabrouty et al. 2013; Morris et al. 2014). GGOH and other isoprenols are converted to pyrophosphate derivatives (Crick et al. 1997), which led us to propose that GGpp is the active component in HMGCR ERAD. The second postubiquitination step is mediated by the 19S regulatory subunit of the proteasome, which contains six AAA-ATPases (Ehlinger and Walters 2013), and involves dislocation of membrane-extracted HMGCR from membranes into the cytosol. Cytosolically dislocated HMGCR is then delivered into the core of the 20S proteasome for proteolysis (Fig. 3).

Figure 3.

Figure 3.

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Model for sterol-accelerated endoplasmic reticulum–associated degradation (ERAD) of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Accumulation of sterols in membranes of the ER triggers binding of Insigs to the membrane domain of HMGCR. Insig binding bridges HMGCR to Insig-associated E3 ubiquitin ligases that combine with their cognate E2s to ubiquitinate HMGCR on lysines-89 and -248. Ubiquitination marks HMGCR for extraction across the ER membrane through a reaction mediated by VCP/p97 and its ubiquitin-binding cofactors. Extracted HMGCR is then dislodged from the membrane by the 19S regulatory particle (19S RP) into the cytosol and delivered into the core of the 26S proteasome for degradation.

The budding yeast Saccharomyces cerevisiae expresses two ER-localized isozymes of HMGCR that are designated Hmg1p and Hmg2p (Hampton et al. 1996a). Hmg1p is a relatively stable protein, whereas Hmg2p is subjected to rapid, metabolically regulated ERAD. Hampton and coworkers have established that the accumulation of GGpp within ER membranes specifically induces the misolfding of the membrane domain of Hmg2p (Garza et al. 2009; Wangeline and Hampton 2018). This misfolding allows entry of Hmg2p into the HRD (HMG CoA reductase degradation) quality control pathway for ubiquitination by the E3 ubiquitin ligase HRD1 and subsequent ERAD (Hampton et al. 1996b; Wangeline et al. 2017). Yeast also express two Insig homologs called Nsg1 and Nsg2 (Flury et al. 2005; Theesfeld and Hampton 2013). The sterol synthesis intermediate lanosterol stimulates binding of Nsg1 and Nsg2 to Hmg2p and stabilizes the enzyme by inhibiting its GGpp-induced ERAD (Theesfeld and Hampton 2013). Despite significant differences in the regulation of Hmg2p and HMGCR, sterol and nonsterol isoprenoids modulate ERAD in both yeast and mammalian systems to control the rate-limiting step in the sterol synthetic pathway.

Mice designated HmgcrKi/Ki harbor K89R/K248R knockin mutations in the endogenous Hmgcr gene (Hwang et al. 2016). HMGCR failed to become ubiquitinated and degraded in livers of HmgcrKi/Ki mice, causing its accumulation. This accumulation was also evident in other tissues of the knockin mice and occurred even though HMGCR mRNA was reduced 50%–60%. This reduction resulted from inhibition of SREBP activation owing to the overaccumulation of cholesterol. When HmgcrKi/Ki mice were fed diets containing cholesterol, activation of SREBP was inhibited and levels of HMGCR mRNA were further reduced. However, HMGCR protein was refractory to accelerated ERAD in livers of cholesterol-fed HmgcrKi/Ki mice. Early studies showed that administration of statins to cholesterol-fed mice caused HMGCR to accumulate in the liver, which was reversed by administration of mevalonate (Kita et al. 1980). Importantly, statin-induced accumulation of HMGCR was blunted (fivefold) in HmgcrKi/Ki mice compared to wild-type controls (Hwang et al. 2016). Together, these studies provide direct evidence that sterol-accelerated ERAD substantially contributes to feedback regulation of HMGCR and cholesterol synthesis in vivo.

IDENTIFYING THE TARGET OF GGPP IN ERAD OF HMGCR

In 2015, we identified UbiA prenyltransferase domain-containing protein-1 (UBIAD1) as an associated protein of HMGCR (Schumacher et al. 2015). UBIAD1 was first identified as a down-regulated transcript in prostate and bladder tumors (McGarvey et al. 2001, 2003) and belongs to the UbiA superfamily of prenyltransferases (Li 2016). These polytopic, integral membrane enzymes transfer isoprenyl groups to aromatic acceptors, producing chlorophylls, ubiquinones, hemes, vitamin E, and vitamin K. UBIAD1 synthesizes a vitamin K2 subtype called menaquinone-4 (MK-4) by using GGpp to prenylate the 1,4-naphthoquinone menadione (MD) derived from side chain cleavage of dietary vitamin K1 (phylloquinone, PK) (Fig. 1; Nakagawa et al. 2010; Hirota et al. 2013). Our interest in UBIAD1 was piqued by studies showing UBIAD1 mutations in the human gene are associated with Schnyder corneal dystrophy (SCD), an autosomal-dominant disease characterized by progressive corneal opacification that reduces visual acuity (Orr et al. 2007; Weiss et al. 2007). Cholesterol overaccumulates in corneas from SCD patients, indicating the disorder results from dysregulation of cholesterol metabolism (McCarthy et al. 1994; Gaynor et al. 1996; Yamada et al. 1998).

Results of our studies showed that UBIAD1 bound to HMGCR through an Insig-dependent reaction that was enhanced by sterols (Schumacher et al. 2015). In contrast, GGpp derived from exogenously added GGOH abrogates sterol-induced binding of UBIAD1 to HMGCR. Dissociation of the HMGCR-UBIAD1 complex enhances ERAD of HMGCR as indicated by the analysis of UBIAD1-deficient cells in which sterols alone maximally stimulated the ERAD of HMGCR (Schumacher et al. 2015). Additional evidence implicating UBIAD1 as an inhibitor of HMGCR ERAD was provided by the analysis of SCD-associated variants of the prenyltransferase. Twenty-four missense mutations in the UBIAD1 gene have been identified in SCD families that alter 20 amino acids in the encoded protein (Nickerson et al. 2013; Nowinska et al. 2014; Lin et al. 2016). SCD-associated mutations in human UBIAD1 correspond to amino acids in archaeal UbiA prenyltransferases that cluster around the enzymes’ membrane-embedded active site (Cheng and Li 2014; Huang et al. 2014; Schumacher and DeBose-Boyd 2021). SCD-associated UBIAD1 is defective in catalyzing MK-4 synthesis likely because of reduced affinity for GGpp (Hirota et al. 2015; Jun et al. 2020). Sterols continue to trigger binding of SCD-associated UBIAD1 to HMGCR, but GGpp fails to dissociate the complex (Schumacher et al. 2015). As a result, ERAD of HMGCR becomes inhibited, which causes the protein's accumulation that leads to enhanced synthesis of cholesterol (Schumacher et al. 2016).

Studies summarized above established that UBIAD1 associates with HMGCR in the ER to inhibit ERAD. However, we discovered that both endogenous and overexpressed UBIAD1 localize to the medial/trans-Golgi of cells replete with sterols and nonsterol isoprenoids (Schumacher et al. 2015). Remarkably, depleting cells of nonsterol isoprenoids using compactin caused UBIAD1 to become sequestered in the ER. GGOH stimulated transport of UBIAD1 to the Golgi of compactin-treated cells, whereas neither FOH, the alcohol derivative of Fpp, nor sterols stimulated Golgi localization of UBIAD1. Protein traffic from the ER to the cis-Golgi membrane requires cargo incorporation into coat protein complex-II (COPII)-coated vesicles that bud from ER membranes (Zanetti et al. 2012; Barlowe and Miller 2013). We used methods that reconstitute in vitro formation of COPII vesicles (Rexach and Schekman 1991; Rowe et al. 1996; Aridor et al. 1998) to show that GGpp, but not Fpp, stimulated incorporation of UBIAD1 from isoprenoid-depleted ER membranes into transport vesicles destined for targeting to the cis-Golgi membrane (Schumacher et al. 2015).

Considered together, our current data is consistent with a model in which UBIAD1 continuously cycles between the Golgi and ER, allowing it to constantly monitor levels of GGpp embedded in ER membranes. Upon sensing depletion of GGpp, UBIAD1 becomes sequestered in the ER, where it binds to and inhibits HMGCR ERAD. This inhibition allows production of mevalonate that is utilized for replenishment of GGpp and other nonsterol isoprenoids (Fig. 4). UBIAD1-mediated sensing of GGpp is defective in SCD as indicated by ER sequestration of SCD-associated UBIAD1 regardless of the presence or absence of GGpp (Fig. 5; Schumacher et al. 2015).

Figure 4.

Figure 4.

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UbiA prenyltransferase domain-containing protein-1 (UBIAD1) coordinates synthesis of sterol and nonsterol isoprenoids by inhibiting endoplasmic reticulum–associated degradation (ERAD) of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Following the action of Insigs, a UBIAD1 binds to a subset of HMGCR molecules, inhibiting their ERAD to allow continued synthesis of mevalonate that is preferentially incorporated into GGpp and other nonsterol isoprenoids. Once sufficient levels of GGpp accumulate, the isoprene binds to UBIAD1, triggering dissociation of the HMGCR-UBIAD1 complex. The GGpp-induced release of UBIAD1 from HMGCR allows for translocation of UBIAD1 from the ER to Golgi and the membrane extraction, cytosolic dislocation, and proteasomal degradation of HMGCR.

Figure 5.

Figure 5.

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Schnyder corneal dystrophy (SCD)-associated UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is sequestered in the endoplasmic reticulum (ER) and inhibits endoplasmic reticulum–associated degradation (ERAD) of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Sterols continue to stimulate binding of SCD-associated UBIAD1 to HMGCR; however, GGpp fails to dissociate the complex. This is due, in part, to reduced affinity of SCD-associated UBIAD1 for GGpp. The failure of SCD-associated UBIAD1 to dissociate from HMGCR leads to inhibition of ERAD, which causes its accumulation and enhances synthesis and intracellular accumulation of cholesterol.

Interestingly, acutely depleting cells of nonsterol isoprenoids causes the rapid, retrograde transport of UBIAD1 from the Golgi to ER (Elsabrouty et al. 2021). This finding indicates pools of GGpp that control intracellular transport of UBIAD1 are subjected to rapid turnover. We showed recently this rapid turnover was mediated by type 1 polyisoprenoid diphosphate phosphatase (PDP1), which dephosphorylates GGpp and other isoprenyl pyrophosphates (Miriyala et al. 2010). Knockdown of PDP1 not only prevented compactin-induced Golgi-to-ER translocation of UBIAD1, but also blocked the compactin-induced stabilization of HMGCR (Elsabrouty et al. 2021). Thus, PDP1 contributes to a pathway for interconversion of isoprenoids and their phosphorylated derivatives that balances the sterol and nonsterol branches of mevalonate metabolism by modulating HMGCR and UBIAD1.

PHYSIOLOGICAL SIGNIFICANCE OF UBIAD1-MEDIATED REGULATION OF HMGCR ERAD

To examine the role of UBIAD1 in regulation of HMGCR ERAD and cholesterol metabolism in vivo, we generated mice designated Ubiad1Ki/Ki, which harbor a knockin mutation that changes asparagine-100 to serine (N100S) (Jo et al. 2019). This mutation corresponds to the SCD-associated N102S mutation in human UBIAD1. HMGCR protein accumulated disproportionately to its mRNA in the liver, cornea, and other tissues of Ubiad1Ki/Ki mice. Consistent with the autosomal-dominant character of SCD, HMGCR protein accumulated in tissues of mice heterozygous for the N100S mutation. Hepatic cholesterol was slightly elevated in Ubiad1Ki/Ki mice; a more substantial increase (300%–400%) in GGOH and ubiquinone-10 was observed. Aged Ubiad1Ki/Ki mice (>50 wk) exhibited signs of corneal opacification. Similarly, Song and coworkers established that knockin mice harboring the SCD-associated G184R mutation overaccumulated HMGCR and hepatic cholesterol and exhibited signs of corneal opacification (Jiang et al. 2019).

The ERAD of HMGCR was more resistant to cholesterol feeding in Ubiad1Ki/Ki mice compared to that in HmgcrKi/Ki mice, because of resistance to both basal and sterol-accelerated degradation (Doolman et al. 2004). Importantly, sterols triggered ubiquitination of HMGCR in mouse embryonic fibroblasts derived from Ubiad1Ki/Ki mice; however, the protein failed to become degraded. These results are consistent with our proposal that UBIAD1 inhibits ERAD of HMGCR by blocking a postubiquitination step in the reaction (see Fig. 5). Similar to results obtained with HmgcrKi/Ki mice (Hwang et al. 2016), the statin-induced accumulation of HMGCR was blunted in livers of Ubiad1Ki/Ki mice. Subcellular fractionation studies showed UBIAD1 localized to the Golgi of livers harvested from wild-type mice that consumed a chow diet (Jo et al. 2019). When the mice were challenged with the statin lovastatin, UBIAD1 became sequestered in ER membranes. UBIAD1 (N100S) remained sequestered in the ER of Ubiad1Ki/Ki livers in both the absence or presence of lovastatin. These findings reveal that GGpp regulates ER-to-Golgi trafficking of UBIAD1 in vivo through similar mechanisms that we previously established in cultured cells.

Vitamin K occurs in various forms that include the provitamin MD, plant-derived PK, and menaquinones (MKs) that are collectively referred to as vitamin K2 and are named according to the number of isoprene units comprising their side chain (i.e., MK-n). UBIAD1 produces MK-4 in invertebrate and vertebrate animals, whereas longer-chain MKs (MK-7, MK-9, and MK-11) are produced by gut bacteria. In mammals, the most well-established function of vitamin K is to serve as a cofactor for the post-translational g-carboxylation of specific glutamate residues in vitamin K–dependent proteins (VKDPs) (Shearer and Newman 2014; Shearer and Okano 2018). This modification is indispensable for biological functions of VKDPs, many of which are required for blood coagulation. VKDPs also mediate additional processes ranging from mineralization of bone and cardiovascular calcification to energy metabolism and inflammation (Booth 2009; Shearer and Okano 2018). Vitamin K has also been reported to have direct effects on expression of genes, signal transduction, and cellular regulation. Attempts were undertaken to generate Ubiad1-deficient mice to elucidate the function of UBIAD1 and MK-4 in vivo (Nakagawa et al. 2014). Unfortunately, homozygous Ubiad1 deficiency led to embryonic lethality, which suggested UBIAD1 and/or MK-4 plays an essential role in development.

In UBIAD1-deficient human fibroblasts, we found that the ERAD of HMGCR was accelerated, which led to reduced synthesis and intracellular accumulation of cholesterol (Schumacher et al. 2018). This led us to postulate that embryonic lethality of Ubiad1 deficiency in mice resulted from depletion of mevalonate-derived metabolites distinct from MK-4. Cholesterol (and likely other sterol and nonsterol isoprenoids) overaccumulates in tissues of HmgcrKi/Ki mice where HMGCR is resistant to ERAD (Hwang et al. 2016). Thus, we reasoned that overproduction of mevalonate-derived products in HmgcrKi/Ki mice would rescue embryonic lethality associated with Ubiad1 deficiency (Fig. 6). We appraised this hypothesis by generating wild-type and HmgcrKi/Ki mice with heterozygous Ubiad1 deficiency; the mice are designated Ubiad1+/− and Ubiad1+/− HmgcrKi/Ki, respectively (Jo et al. 2020). Intercrosses between Ubiad1+/− mice produced wild-type and Ubiad1+/− offspring at a 1:2 ratio; Ubiad1−/− offspring were not produced as expected. In contrast, all expected genotypes (Ubiad1+/+ HmgcrKi/Ki, Ubiad1+/− HmgcrKi/Ki, and Ubiad1−/− HmgcrKi/Ki) were obtained at a 1:2:1 ratio upon intercrossing Ubiad1+/− HmgcrKi/Ki mice. These finding provides unequivocal genetic evidence that UBIAD1 is an inhibitor of HMGCR ERAD and confirmed that abrogating the reaction allows production of one or more mevalonate-derived metabolites that rescue embryonic lethality associated with Ubiad1 deficiency.

Figure 6.

Figure 6.

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Ubiquitination-resistant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) rescues embryonic lethality of Ubiad1 deficiency in mice. In wild-type mice, UbiA prenyltransferase domain-containing protein-1 (UBIAD1) inhibits the endoplasmic reticulum–associated degradation (ERAD) of HMGCR to coordinate synthesis of sterol and nonsterol isoprenoids. Genetic ablation of Ubiad1 enhances ERAD of HMGCR, resulting in depletion of mevalonate-derived products that are essential for development. This ERAD is blocked in knockin mice (designated HmgcrKi/Ki) expressing ubiquitination-resistant HMGCR, which rescues embryonic lethality of Ubiad1 deficiency. The red X denotes mutations of lysines 89 and 248 that prevent sterol-induced ubiquitination and ERAD of HMGCR.

Despite the absence of UBIAD1 and its enzymatic product, MK-4, Ubiad1−/− HmgcrKi/Ki mice did not exhibit signs of vitamin K deficiency such as excessive hemorrhaging. It is likely that vitamin K activity required for γ-carboxylation of coagulation factors in the Ubiad1 deficient mice was provided by the diet and/or microbiota of the gut. To begin understanding the in vivo function of MK-4, a complete histological examination of all tissues from Ubiad1−/− HmgcrKi/Ki mice was conducted. Abnormalities were observed in only two tissues of the Ubiad1- deficient animals—skeletal muscle and bone. The mice displayed several hallmarks of muscle injury and dysregulation of bone homeostasis. These include degenerating skeletal muscle myofibers with macrophage infiltration, myofibers containing centrally localized nuclei, severe cellular disorganization within the femoral growth plate, and a decrease in the number of boney trabeculae. Moreover, serum analysis of Ubiad1−/− HmgcrKi/Ki mice revealed elevated levels of aminotransferases, lactate dehydrogenase, and creatine kinase as well as reduced alkaline phosphatase.

The bone phenotype of Ubiad1−/− HmgcrKi/Ki mice is consistent with the observation that MK-4 binds to and activates the nuclear receptor pregnane X receptor (PXR) (Tabb et al. 2003). Germline knockout of Pxr in mice leads to reduced bone formation and increased bone absorption (Azuma et al. 2010). Thus, it will be important to determine whether bone abnormalities observed in Ubiad1−/− HmgcrKi/Ki mice are similar to those in Pxr-deficient mice. The skeletal muscle phenotype may have important implications for patients that develop myopathy during statin therapy (Thompson et al. 2003; Ward et al 2019). The disorder has been attributed to depletion of mevalonate-derived metabolites owing to the inhibition of HMGCR. Interestingly, mice harboring skeletal muscle–specific knockout of HMGCR also develop myopathy, which can be rescued by mevalonate administration (Osaki et al. 2015). The muscle injury observed in Ubiad1−/− HmgcrKi/Ki suggests the intriguing possibility that depletion of MK-4 contributes to statin-induced myopathy in humans.

CONCLUSION AND OUTSTANDING QUESTIONS

In this review, we summarize how the ERAD pathway is utilized in the feedback control of HMGCR and, ultimately, the synthesis of sterol and nonsterol isoprenoids. Despite several major breakthroughs including the discovery of a role for UBIAD1 in HMGCR ERAD and demonstration of the significance of ERAD in regulation of HMGCR in vivo, several questions remain. For example, the mechanism through which ERAD of HMGCR is initiated has not been completely resolved. Cholesterol synthesis intermediates (lanosterol and 24,25-dihydrolanosterol [DHL]) as well as oxysterols such as 25-hydroxycholesterol (25HC) stimulate Insig-mediated ubiquitination and ERAD of HMGCR. Current evidence suggest that oxysterols directly bind to Insigs, which stimulates their binding to both Scap and HMGCR (Radhakrishnan et al. 2007). In contrast, lanosterol and DHL do not bind Insigs and cannot trigger their binding to Scap (Song et al. 2005b; Radhakrishnan et al. 2004, 2007). It is likely that lanosterol and DHL accelerate ERAD by directly binding HMGCR; however, this binding has yet to be reported.

Another open question is the mechanism through which GGpp modulates ER-to-Golgi trafficking of UBIAD1. We speculate that binding of GGpp to UBIAD1 induces a conformational change that exposes a binding site for COPII that allows its incorporation into transport vesicles. Alternatively, GGpp binding could allow UBIAD1 to associate with an escort protein that facilitates incorporation of UBIAD1 into COPII vesicles.

UBIAD1 inhibits the ERAD of HMGCR by blocking a postubiquitination step in the reaction as indicated by the observation that HMGCR becomes ubiquitinated in MEFs derived from Ubiad1Ki/Ki mice despite inhibition of ERAD (Jo et al. 2019). We consider it likely that UBIAD1 inhibits recruitment of VCP/p97 to ubiquitinated HMGCR; alternatively, the prenyltransferase may inhibit another reaction required for membrane extraction of HMGCR. Efforts are currently underway to elucidate mechanisms for UBIAD1-mediated inhibition of HMGCR ERAD.

Finally, MK-4 accumulates differentially in mouse tissues; high levels of the vitamin K2 subtype are found in the pancreas, thyroid, adrenal, testes, brain, and adipose tissue (Okano et al. 2008; Harshman et al. 2016; Jo et al. 2020). However, the precise roles MK-4 plays in these tissues are completely unknown. Does the tissue distribution of MK-4 relate to its role in the γ-carboxylation of VKDPs and/or its carboxylation-independent functions? To understand the physiological significance of tissue-specific synthesis of MK-4, the function of UBIAD1 as an MK-4 synthetic enzyme and regulator of HMGCR ERAD must be dissociated. This can only be accomplished in HmgcrKi/Ki mice where the functions of UBIAD1 in regulating HMGCR ERAD and synthesizing MK-4 are dissociated.

COMPETING INTEREST STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

Research described in this review was supported by National Institutes of Health Grants HL-20948, GM-134700, and GM0144039 (to R.A.D.-B.).

Footnotes

Editors: Susan Ferro-Novick, Tom A. Rapoport, and Randy Schekman

Additional Perspectives on The Endoplasmic Reticulum available at www.cshperspectives.org

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