Mevalonate metabolism governs cancer immune surveillance

Abstract

The metabolic reprogramming that drives immunity engages the mevalonate pathway for cholesterol biosynthesis and protein prenylation. The importance of tight regulation of this metabolic route is reflected by the fact that too low activity impairs cellular function and survival, whereas hyperactivity can lead to malignant transformation. Here, we first address how mevalonate metabolism drives immunity and then highlight ways of the immune system to respond to both, limited and uncontrolled flux through the mevalonate pathway. Immune responses elicited by mevalonate pathway dysregulation may be harnessed to increase the clinical efficacy of current cancer therapy regimens.

Keywords: ATP citrate lyase; HMG-CoA reductase; T lymphocytes; cancer; cholesterol; dendritic cells; flux; immunometabolism; macrophages; mevalonate; protein prenylation.

Figure 1.

The SREBP-driven mevalonate pathway. The transcriptional activity of sterol regulatory element-binding proteins (SREBPs) governs expression of mevalonate pathway enzymes. ATP citrate lyase (ACLY, EC 2.3.3.8), which can be inhibited by hydroxycitrate (HC), generates cytosolic acetyl-coenzyme A (acetyl-CoA). 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)-synthase (HMGCS1, EC 2.3.3.10) condenses 3 molcules of acetyl-CoA to form HMG-CoA. HMG-CoA reductase (HMGCR, EC 1.1.1.34), which can be inhibited by statins, in turn generates mevalonate (also known as mevalonic acid) in the first committed step of the pathway. Sequential phosphorylation reactions by mevalonate kinase (MVK, EC 2.7.1.36), which is mutated in MVK deficiency, and phosphomevalonate kinase (PMVK, EC 2.7.4.2), respectively, followed by a decarboxylation step catalyzed by mevalonate diphosphate decarboxylase (MVD, EC 4.1.1.33) produce isopentenyl diphosphate (IPP). Farnesyl diphosphate (FPP) synthase (FDPS, EC 2.5.1.10), which is the target of nitrogen-containing bisphosphonates (N-BPs) condenses IPP (C₅) and its isomer dimethylallyl diphosphate (DMAPP, C₅) to form geranyl diphosphate (GPP, C₁₀) and subsequently GPP with another IPP unit to generate FPP (C₁₅). FPP is the common precursor for cholesterol and steroids in the sterol branch as well as for products of the nonsterol branch including geranylgeranyl diphosphate (GPPP, C₂₀), dolichol, heme A and ubiquinone (coenzyme Q). GGPP is formed by GGPP synthase (GGPS, EC 2.5.1.29) through condensation of FPP with yet another IPP unit. In protein prenylation, FPP and GGPP, serve as prenyl group donors in posttranslational modifications of multiple Ras protein family members and G protein-coupled receptors. Farnesylation (using FPP) or geranylgeranylation (using GGPP) are required for membrane attachment and function of these proteins. Prenylated proteins constitute approximately 0.5% to 2% of proteins in mammalian cells. Prenyldiphosphate synthase-1 (PDSS1, EC 2.5.1.91) catalyzes the elongation of GPP or FPP with several IPP moieties to form the polyisoprenoid chain of ubiquinone (coenzyme Q). ACAT1 catalyzes cholesterol esterification for storage purposes.

Figure 2.

The metabolic reprogramming associated with immune cell activation engages the mevalonate pathway. Immune cell stimulation activates the PI3K-AKT-mTOR pathway and promotes uptake of glucose via glucose transporter (GLUT) proteins followed by glycolysis and oxidation of glucose-derived pyruvate in the mitochondrial tricarboxylic acid cycle (TCA) cycle, which drives oxidative phosphorylation (OXPHOS). Activated immune cells also export citrate to the cytosol, where it is converted back to acetyl-coenzyme A (acetyl-CoA) by ATP citrate lyase (ACLY). Cytosolic acetyl-CoA serves as a metabolic precursor not only for fatty acid (FA) synthesis and protein acetylation but also for mevalonate metabolism (the lipogenic pathways). mTOR signaling also leads to the activation of sterol regulatory element-binding proteins (SREBP), which are the main transcription factor for mevalonate pathway-associated genes in immune cells. In a feed-forward loop, enhanced mevalonate metabolism facilitates prenylation of Ras proteins and thus further enhances pathway activity. In an apparently futile cycle of concurrent synthesis and oxidation, de novo synthesized fatty acids (FA) are stored in the lysosome. Lysosomal acid lipase (LAL) catalyzes the release of these FA, which are shuttled into the mitochondria for ATP generation through ß-oxidation.

Figure 3.

Inflammatory and immune responses to mevalonate pathway dysregulation. The responses induced by restricted flux have been studied using pharmacological inhibitors (statins and nitrogen-containing bisphosphonates, N-BPs), caloric restriction mimetics (CRM) such as hydroxycitrate (see also Fig. 1) or by genetic inactivation of geranylgeranyltransferase (GGTase), mevalonate kinase (MVK) or SREBP cleavage-activating protein (SCAP). Enhanced or uncontrolled flux can result from gain-of-function p53 mutation, sustained NFkB activation associated with chronic inflammation, ectopic expression of HMG-CoA reductase, or possibly also by futile metabolic constellations. Cell longevity resulting from sustained mevalonate metabolism and protein prenylation may physiologically be important for T cell memory establishment or pathologically manifest as malignant transformation. Among the various tools currently available for mevalonate pathway manipulation, N-BPs are unique, since they increase levels of IPP and simultaneously inhibit protein prenylation. Vγ9Vδ2 T cells, which are activated by increased levels of IPP and other mevalonate pathway intermediates, are intended to perform broad immune surveillance of enhanced mevalonate metabolism.

Figure 4.

Extracellular mevalonate metabolism. Intracellular accumulation of mevalonate derivatives triggers homeostatic mechanisms leading to their export into the extracellular space. In dendritic cells (DC), the ATP-binding cassette transporter A1 (ABCA1) not only mediates efflux of cholesterol, which arises from IPP, but also exports IPP itself, which acts as an agonist of Vγ9Vδ2 T cells (“phosphoantigen,” pAg). In the extracellular environment, pAgs can bind to apoA-I, which facilitates pAg presention by butyrophilin 3A1 (BTN3A1) on the DC surface to Vγ9Vδ2 T cells. The ecto-ATPase CD39 also exhibits intrinsic isoprenoid diphosphate phosphohydrolase activity and may control strength and duration of antigen presentation through the hydrolytic inactivation of pAgs. Finally, scavenger receptors such as CD36 may internalize not only IPP-derived CoQ₁₀ but also IPP itself.