Figure 2.
Mevalonate metabolism in immune and cancer cells. (A) Fatty acid metabolism makes the difference. Immune cells that realize effector functions depend on Myc-driven glycolysis that fuels lipogenesis. These cells engage mevalonate metabolism and fatty acid synthesis (FAS) but refrain from fatty acid oxidation (FAO). Unfortunately, cancer stem cells may have similar metabolic profiles. Although regulatory immune cells may still require Myc-driven glycolysis and FAS to some extent, they also engage FAO, which may occur at the expense of mevalonate pathway activity. These cells use FAO to realize their suppressive functions and to support survival. Distinct tumor types adopt a similar metabolic profile. In these cells, FAO may limit the availability of acetyl-CoA for mevalonate metabolism rendering it a potential Achilles’ heel-like target for therapeutic interventions. (B) Transcellular mevalonate metabolism. Starvation or p53 gain-of-function mutations lead to enforced uptake and use of extracellular isoprenoids in tumor cells. Intracellularly accumulating isopentenyl diphosphate (IPP) can bind to the B30.2 domain of butyrophilin 3A1 (BTN3A1), which leads to the activation of Vγ9Vδ2 T cells through a conformational change of the extracellular domain. In dendritic cells (DCs), the cholesterol efflux transporter adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) may export mevalonate-derived IPP into the extracellular space. Extracellular IPP can bind to BTN3A1 on the DC cell surface resulting in the activation of Vγ9Vδ2 T cells. The ecto-ATPase CD39 is able to dephosphorylate IPP thus limiting the duration and strength of IPP-induced γδ T cell responses. The lipid scavenger CD36 may also mediate the uptake of extracellular isoprenoids. Cholesterol storage through ACAT-1-mediated esterification may limit T cell activity. (C) Training of mevalonate metabolism. Priming of monocytes with Bacillus Calmette–Guérin (BCG) or β-glucan leads to an Akt–mTOR-driven metabolic reprogramming that empowers these cells to respond to subsequent challenges with increased production of cytokines and reactive oxygen intermediates. This increased responsiveness represents a form of innate memory and is based on enhanced flux through the mevalonate pathway. Significantly upregulated reactions include the production of acetoacetyl-CoA (ACAT-1), phosphomevalonate, farnesyl diphosphate as well as squalene and 2,3 oxidosqualene, the latter being rate-limiting steps of cholesterol biosynthesis. Overall, more than 50% of the genes in the pathway are activated in trained cells.