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Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-β–deficient neutrophils in a congenital neutropenia syndrome
- Publication Year :
- 2010
- Publisher :
- American Society of Hematology, 2010.
-
Abstract
- G6PC3 deficiency, characterized by neutropenia and neutrophil dysfunction, is caused by deficiencies in the endoplasmic reticulum (ER) enzyme glucose-6-phosphatase-β (G6Pase-β 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-β in neutrophils remains unknown. We hypothesized that the ER recycles G6Pase-β–generated glucose to the cytoplasm, thus regulating the amount of available cytoplasmic glucose/G6P in neutrophils. Accordingly, a G6Pase-β 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 p47phox are down-regulated in murine and human G6PC3-deficient neutrophils. The results establish that in nonapoptotic neutrophils, G6Pase-β is essential for normal energy homeostasis. A G6Pase-β deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil dysfunction.
- Subjects :
- Male
Cytoplasm
Neutropenia
Adolescent
Neutrophils
Glucose uptake
Immunology
G6PC3
Apoptosis
Pentose phosphate pathway
Glycogen Storage Disease Type I
Endoplasmic Reticulum
Biochemistry
Phagocytes, Granulocytes, and Myelopoiesis
Mice
Adenosine Triphosphate
Stress, Physiological
medicine
Animals
Humans
Lactic Acid
Annexin A5
Child
Mice, Knockout
Glucose Transporter Type 1
NADPH oxidase
biology
Caspase 3
Endoplasmic reticulum
NADPH Oxidases
Cell Biology
Hematology
Syndrome
medicine.disease
Cell biology
Mice, Inbred C57BL
Glucose
biology.protein
Unfolded protein response
Glucose-6-Phosphatase
Female
Glucose 6-phosphatase
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....65e82107ce0fdf0f3c87481ab1bb1fb7