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Review
. 2016 Sep;51(5):359-378.
doi: 10.1080/10409238.2016.1215288. Epub 2016 Aug 5.

The PI3K Pathway in B Cell Metabolism

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Free PMC article
Review

The PI3K Pathway in B Cell Metabolism

Julia Jellusova et al. Crit Rev Biochem Mol Biol. .
Free PMC article

Abstract

B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprograming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor-mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes.

Keywords: Akt; glycolysis; lymphocyte; mTOR; mitochondria.

Figures

Figure 1
Figure 1. Regulation of cell metabolism by the PI3K/Akt signaling pathway
Akt is one of the main effector molecules downstream of PI3K and regulates various metabolic processes by phosphorylating enzymes such as ACLY, which is needed for lipid synthesis, or HK2 and PFK2, which are involved in glycolysis. Akt can also indirectly affect cell metabolism by regulating the activity of mTORC1 or GSK3.
Figure 2
Figure 2. Major metabolic pathways that support ATP production and biosynthesis in lymphocytes
Glucose is metabolized to pyruvate through glycolysis and can be further converted to lactate, which is then secreted. This process does not require oxygen and the net gain in energy is 2 ATP molecules per molecule glucose. Alternatively, pyruvate can be oxidized to Acetyl-CoA and enter the TCA cycle. The NADH and FADH2 molecules produced in the TCA cycle are then used as electron donors in the electron transport chain (oxidative phosphorylation) to generate ATP. If glucose is metabolized completely through oxidative phosphorylation, the net energy gain is approximately 36 ATP molecules per molecule glucose. Carbon atoms from molecules other than glucose can also enter the TCA cycle. Fatty acids need to be activated in the cytosol and transferred across the mitochondrial membrane before being oxidized in the mitochondria. Catabolic pathways are highlighted in green. Anabolic pathways are highlighted in red. In blue are shown some of the enzymes catalyzing important steps in cell metabolism. Abbreviations: ACC= Acetyl-CoA-carboxylase, ACLY= ATP citrate lyase, F6P= Fructose 6-phosphate, F1,6BP= Fructose 1,6-bisphosphate, FAS= fatty acid synthase, G6P= Glucose 6-phosphate, HK=hexokinase, LDHA= Lactate dehydrogenase A, PDH= Pyruvate dehydrogenase, PDHK= Pyruvate dehydrogenase kinase, PFK= Phosphofructokinase, TCA cycle = Tricarboxylic acid cycle
Figure 3
Figure 3. The production and function of reactive oxygen species in B cells
ROS can be produced in B cells as a byproduct of mitochondrial function and by NADPH oxidases. It has been suggested that the Nox2-containing NADPH oxidase complex is responsible for the majority of ROS production in B cells. However the calcium- regulated NADPH oxidase Duox1 may play a role in specific B cell subsets (Singh et al., 2005). Furthermore, the phenotypes of mice deficient in Ncf1 (an essential part of the Nox2 complex) or gp91phox (catalytic subunit of Nox2) differ from mice lacking the voltage-gated proton channel HVN1, which plays a role in maintaining NADPH oxidase activity (Wheeler and Defranco, 2012, Capasso et al., 2010, Richards and Clark, 2009). Thus, the exact mechanism of ROS production in B cells awaits further clarification. ROS produced downstream of the BCR serves as a signaling molecule and can affect B cell activation and function. Several lines of evidence suggest that Syk and the PI3K signaling pathways are activated in response to ROS, however the exact mechanism is not completely understood yet. Mitochondrial ROS can also affect cell fate by inhibiting Heme synthesis. Heme is known to inhibit Bach2 function and thereby relieving Bach2 mediating Blimp repression. Thus, increased ROS production can inhibit plasma cell development and favor class switch recombination by modulating Bach2 function. While ROS seems to contribute to B cell signaling and is essential for BCR mediated proliferation, excessive ROS production can lead to cell damage and ultimately to cell death. Abbreviations: ALA= Aminolevulinic acid, CoPIII= coproporphyrinogen III, mtDNA= mitochondrial DNA, PIX= protoporphyrin IX, SCoA= Succinyl coenzyme A.

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