Gamma-interferon Inducible Lysosomal Thiol Reductase, Its Secretion and Role in Bacterial Infection

Gamma-interferon inducible lysosomal thiol reductase (GILT) is a unique thioredoxin that reduces disulfide bonds at acidic pH. GILT can be found in the lysosome in its mature form or secreted as a precursor, both of which are active enzymes. Precursor GILT is constitutively secreted into the murine peritoneal extracellular space. Along with the fully glycosylated precursor, multiple underglycosylated GILT precursors are detected in mouse peritoneal fluid and human ascites, indicating an extracellular mechanism of differential deglycosylation in the peritoneal environment. Bacterial infection induces a time-dependent surge in the peritoneal extracellular GILT levels, which, based on in vitro experiments, is largely contributed by peritoneal macrophages. These findings suggest an extracellular role for GILT both in physiological processes and during inflammation. GILT-deficient peritoneal macrophages produce less reactive oxygen species (ROS) in response to bacterial infection, and exhibit delayed bacterial clearance during the early phase of infection. NADPH oxidase inhibitor treatment negates the difference in bacteria-induced ROS generation, suggesting that GILT regulates NADPH oxidase-dependent ROS production. A proteomics screen has uncovered interesting GILT substrates, offering insights into the potential mechanism for GILT on phagosomal ROS production, as well as its function in the extracellular space.