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T lymphocyte regulation by mevalonate metabolism

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Science Signaling  31 Mar 2015:
Vol. 8, Issue 370, pp. re4
DOI: 10.1126/scisignal.2005970

Figures

  • Fig. 1 Metabolic pathways that support T cell activation.

    In resting cells, glucose-derived pyruvate is converted to acetyl-CoA in mitochondria, and it is fully oxidized in the TCA cycle and through OXPHOS to maximize ATP generation. In contrast, proliferating T cells enhance glycolysis but also export citrate to the cytosol, where it is converted back to acetyl-CoA and serves as a metabolic precursor for fatty acid biosynthesis and mevalonate metabolism. To ensure metabolic flux, activated T cells also increase the amount of both glutamine oxidation and glycolysis. The process of glutaminolysis represents a metabolic shunt that converts glutamine into α-KG for subsequent introduction into the TCA cycle. In addition, reductive carboxylation of α-KG (the reverse of what occurs to α-KG in the TCA cycle) for the subsequent synthesis of citrate and acetyl-CoA may also occur in the cytoplasm of activated T cells, preferentially in microenvironments with low oxygen, such as secondary lymphoid organs, inflamed tissues, and tumors. Glucose-6-P, glucose-6-phosphate; 3PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate.

  • Fig. 2 Mevalonate metabolism.

    In the first committed step of the pathway, HMG-CoA reductase, the target of statins, catalyzes the formation of mevalonate. Two kinases and a decarboxylase then sequentially convert mevalonate into IPP, whereas an isomerase catalyzes the interconversion of IPP and its isomer, DMAPP. FPP synthase catalyzes sequential condensation reactions with DMAPP and two units of IPP to form FPP, which is the common substrate for the indicated biosynthetic branches. Finally, GGPP synthase catalyzes another condensation reaction with IPP to form GGPP. Farnesyltransferases and geranylgeranyltransferases use FPP and GGPP, respectively, as activated isoprenoid substrates in the posttranslational prenylation of proteins. By inhibiting FPP synthase, N-BPs cause the depletion of downstream FPP and GGPP (and thus inhibit protein prenylation) as well as the accumulation of IPP, a phosphoantigen that is specifically recognized by certain γδ T lymphocytes (Vγδ9V2 T cells). Mevalonate-P, mevalonate-5-phosphate.

  • Fig. 3 Prenylated proteins in T cell activation.

    (A) The two best-studied effector pathways that are activated by RAS in response to the stimulation of T cells through the TCR or by cytokines are the RAF-MEK-MAPK signaling cascade and the PI3K-AKT-mTOR pathway. AKT can also phosphorylate cellular proteins in a process that results in the inhibition of p53. This AKT-dependent pathway might also abolish the suppressive effect that p53 has on mevalonate metabolism. Because Ras depends on farnesylation to become active, statins, which inhibit mevalonate metabolism at an early stage, or specific farnesyltransferase inhibitors (FTI) block these effector pathways and thus inhibit T cell activation, proliferation, and cytokine production. (B) The TCR-stimulated activation of RhoA and Rac2 results in T cell proliferation, whereas the activation of Rac1 and Cdc42 is required for cytoskeletal dynamics. Inhibition of geranylgeranylation by statins or specific geranylgeranyltransferase inhibitors (GGTIs) results in the inactivation of Rho GTPases and the abrogation of T cell responses. (C) Membrane trafficking of vesicles elicited by T cell activation involves Rab proteins, which are often doubly geranylgeranylated. Genetic inactivation of Rab proteins or of geranylgeranyltransferase (GGT) prevents proper T cell activation and effector function. IL-2R, IL-2 receptor.

  • Fig. 4 Regulation of γδ T cells by mevalonate metabolites: A special case.

    In the case of Vγ9Vδ2 T cells, the mevalonate pathway provides not only metabolites but also multiple TCR agonists (IPP, DMAPP, GPP, FPP, and GGPP). These mevalonate metabolites may thus play a dual role as cell-extrinsic and cell-intrinsic cues. (A) When mevalonate metabolites accumulate in target cells, for example, in tumor cells that bear a mutated p53 protein and thus have an enhanced mevalonate metabolism, they may bind to BTN3A1 and mediate its translocation to the plasma membrane, which leads to the engagement of the Vγ9Vδ2 TCR on Vδ2 T cells. Stimulation of this TCR leads to rapid, innate cell–like effector functions, including IFN-γ production and target cell killing. (B) In addition, cell-intrinsic FPP and GGPP in Vγ9Vδ2 T cells may serve as isoprenoid precursor units in the biosynthesis of cholesterol, oxysterols, steroids, ubiquinone, and prenylated proteins, which thus contribute to the regulation of Vγ9Vδ2 T cell function at a range of different levels.

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