T lymphocyte regulation by mevalonate metabolism

Abstract

Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to tumor cells, shift metabolic activity to aerobic glycolysis, which also fuels mevalonate metabolism. Both sterol and nonsterol derivatives of mevalonate affect T cell function. The intracellular availability of sterols, which is dynamically regulated by different classes of transcription factors, represents a metabolic checkpoint that modulates T cell responses. The electron carrier ubiquinone, which is modified with an isoprenoid membrane anchor, plays a pivotal role in OXPHOS, which supports the proliferation of T cells. Isoprenylation also mediates the plasma membrane attachment of the Ras, Rho, and Rab guanosine triphosphatases, which are involved in T cell immunological synapse formation, migration, proliferation, and cytotoxic effector responses. Finally, multiple phosphorylated mevalonate derivatives can act as danger signals for innate-like γδ T cells, thus contributing to the immune surveillance of stress, pathogens, and tumors. We highlight the importance of the mevalonate pathway in the metabolic reprogramming of effector and regulatory T cells.

T cell metabolism drives immunity

“…Lipids or fatty acids encompass another critical substrate group for T cells. They are a vital component of cell membranes, provide a high yielding energy source, and can also supply substrates for cell signaling and PTMs (Lochner et al, 2015;Thurnher and Gruenbacher, 2015). After T cell activation, the demand for lipids rapidly increases.…”

“…c-Myc and mTOR have important roles in coordinating these metabolic changes Yang et al, 2013), and SREBP transcription factors are critical for reprogramming lipid metabolism (Kidani et al, 2013). SREBPs induce expression of genes involved in FAS and mevalonate pathways, which supply de novo synthesized fatty acids and cholesterol, respectively (Thurnher and Gruenbacher, 2015). CD4 T cells deficient in Raptor, and thus mTORC1 signaling, have impaired de novo FAS, most likely caused by reduced expression of SREBP1 and SREBP2 protein .…”

Innovations in asthma therapy: is there a role for inhaled statins?

“…Since these pathogenic mechanisms occur in asthma, perturbation of the MA pathway likely affects disease pathogenesis [29,70]. Metabolites of the MA cascade play a critical role in cell physiology, and therefore, play a fundamental role in disease [29,72,75]; and statins have the capacity to rectify this imbalance in cells and tissues.…”

Small Drops Get Fat: Unexpected Fatty Acid in Cytoplasmic Lipid Droplets

“…Although inefficient and aberrant at first glance, such metabolism appears to be important for memory T cells to generate ATP and maintain long-term cell survival. It is noteworthy that acetyl-CoA not only serves as a precursor of fatty acid biosynthesis but also fuels the growth and survival-promoting mevalonate pathway (Thurnher and Gruenbacher, 2015). In protein prenylation, mevalonate-derived farnesyl and geranylgeranyl diphosphates represent activated forms of the farnesyl and geranylgeranyl units that are covalently attached to members of the Ras superfamily, including those implicated in cell survival and proliferation (Thurnher and Gruenbacher, 2015).…”

“…It is noteworthy that acetyl-CoA not only serves as a precursor of fatty acid biosynthesis but also fuels the growth and survival-promoting mevalonate pathway (Thurnher and Gruenbacher, 2015). In protein prenylation, mevalonate-derived farnesyl and geranylgeranyl diphosphates represent activated forms of the farnesyl and geranylgeranyl units that are covalently attached to members of the Ras superfamily, including those implicated in cell survival and proliferation (Thurnher and Gruenbacher, 2015). In this context, the present work by Guijas et al also raises the intriguing question of whether macrophages in atherosclerotic lesions might use the futile cycle to promote self-renewal (Robbins et al, 2013), thus leading to the non-resolving inflammatory response that characterizes atherogenesis.…”