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lüll Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-beta-deficient neutrophils in a congenital neutropenia syndrome Jun HS; Lee YM; Cheung YY; McDermott DH; Murphy PM; De Ravin SS; Mansfield BC; Chou JYBlood 2010[Oct]; 116 (15): 2783-92G6PC3 deficiency, characterized by neutropenia and neutrophil dysfunction, is caused by deficiencies in the endoplasmic reticulum (ER) enzyme glucose-6-phosphatase-beta (G6Pase-beta or G6PC3) that converts glucose-6-phosphate (G6P) into glucose, the primary energy source of neutrophils. Enhanced neutrophil ER stress and apoptosis underlie neutropenia in G6PC3 deficiency, but the exact functional role of G6Pase-beta in neutrophils remains unknown. We hypothesized that the ER recycles G6Pase-beta-generated glucose to the cytoplasm, thus regulating the amount of available cytoplasmic glucose/G6P in neutrophils. Accordingly, a G6Pase-beta deficiency would impair glycolysis and hexose monophosphate shunt activities leading to reductions in lactate production, adenosine-5'-triphosphate (ATP) production, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Using annexin V-depleted neutrophils, we show that glucose transporter-1 translocation is impaired in neutrophils from G6pc3(-/-) mice and G6PC3-deficient patients along with impaired glucose uptake in G6pc3(-/-) neutrophils. Moreover, levels of G6P, lactate, and ATP are markedly lower in murine and human G6PC3-deficient neutrophils, compared with their respective controls. In parallel, the expression of NADPH oxidase subunits and membrane translocation of p47(phox) are down-regulated in murine and human G6PC3-deficient neutrophils. The results establish that in nonapoptotic neutrophils, G6Pase-beta is essential for normal energy homeostasis. A G6Pase-beta deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil dysfunction.|Adenosine Triphosphate/metabolism[MESH]|Adolescent[MESH]|Animals[MESH]|Annexin A5/metabolism[MESH]|Apoptosis[MESH]|Caspase 3/metabolism[MESH]|Child[MESH]|Cytoplasm/metabolism[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Female[MESH]|Glucose Transporter Type 1/metabolism[MESH]|Glucose-6-Phosphatase/genetics/*metabolism[MESH]|Glucose/*metabolism[MESH]|Glycogen Storage Disease Type I/genetics/*metabolism/pathology[MESH]|Humans[MESH]|Lactic Acid/metabolism[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|NADPH Oxidases/metabolism[MESH]|Neutropenia/*congenital/genetics/*metabolism/pathology[MESH]|Neutrophils/*metabolism/pathology[MESH]|Stress, Physiological[MESH]|Syndrome[MESH] |