Figure 6.

Proposed mechanisms that underlie neutrophil dysfunction in GSD-Ib. Glucose transported into the cytoplasm via GLUT1 is metabolized by HK to G6P, which participates in 3 major pathways: glycolysis, the HMS, and ER cycling. In cycling, G6P enters the ER via G6PT, where it can accumulate until it is hydrolyzed to glucose by G6Pase-β and transported back into the cytoplasm. By limiting the cytoplasmic glucose/G6P availability, cycling regulates the other 2 cytoplasmic pathways for G6P metabolism. Disruption of ER cycling in G6PT-deficient neutrophils results in reduced glucose uptake and impaired energy homeostasis and functionality. The underlying cause of neutropenia in GSD-Ib is enhanced neutrophil ER stress and oxidative stress.¹⁰ The increases in Hsp90 and ROS in G6PT-deficient neutrophils stabilize HIF-1α, an upstream activator of PPAR-γ. The increase in PPAR-γ downregulates neutrophil respiratory burst, chemotaxis, and calcium mobilization activities. GLUT1, responsible for the transport of glucose in and out of the cell, is shown embedded in the plasma membrane. The G6PT, responsible for the transport of G6P into the ER, and G6Pase-β, responsible for hydrolyzing G6P to glucose and phosphate, are shown embedded in the ER membrane. Thick arrows indicate the changes caused by a defect in G6PT activity.