Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta.
Neutropenia and neutrophil dysfunction are common in many diseases, although their etiology is often unclear. Previous views held that there was a single ER enzyme, glucose-6-phosphatase-alpha (G6Pase-alpha), whose activity--limited to the liver, kidney, and intestine--was solely responsible for the final stages of gluconeogenesis and glycogenolysis, in which glucose-6-phosphate (G6P) is hydrolyzed to glucose for release to the blood. Recently, we characterized a second G6Pase activity, that of G6Pase-beta (also known as G6PC), which is also capable of hydrolyzing G6P to glucose but is ubiquitously expressed and not implicated in interprandial blood glucose homeostasis. We now report that the absence of G6Pase-beta led to neutropenia; defects in neutrophil respiratory burst, chemotaxis, and calcium flux; and increased susceptibility to bacterial infection. Consistent with this, G6Pase-beta-deficient (G6pc3-/-) mice with experimental peritonitis exhibited increased expression of the glucose-regulated proteins upregulated during ER stress in their neutrophils and bone marrow, and the G6pc3-/- neutrophils exhibited an enhanced rate of apoptosis. Our results define a molecular pathway to neutropenia and neutrophil dysfunction of previously unknown etiology, providing a potential model for the treatment of these conditions.
Cheung
Yuk Yin
YY
Section on Cellular Differentiation, Heritable Disorders Branch, National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland 20892, USA.
Kim
So Youn
SY
Yiu
Wai Han
WH
Pan
Chi-Jiunn
CJ
Jun
Hyun-Sik
HS
Ruef
Robert A
RA
Lee
Eric J
EJ
Westphal
Heiner
H
Mansfield
Brian C
BC
Chou
Janice Y
JY
D000818:Animals; D001424:Bacterial Infections / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D001786:Blood Glucose / Q000032:analysis; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005952:Glucose-6-Phosphatase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D006706:Homeostasis; D051379:Mice; D009503:Neutropenia / Q000201:enzymology / Q000235:genetics*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D010538:Peritonitis / Q000201:enzymology / Q000235:genetics* / Q000382:microbiology; D021122:Protein Subunits / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
D001786:Blood Glucose; D021122:Protein Subunits; D019298:Glucose-6-Phosphate; D005952:Glucose-6-Phosphatase; C519262:glucose-6-phosphatase-beta, mouse