Moreover, IRGs and GBPs play roles in host defense against vacuole-forming bacteria, including Salmonella, Chlamydia, Mycobacteria, and Listeria, by induction of antibacterial responses involving autophagic effectors, inflammasomes, and phagocytic oxidases ( 4 – 6). MX proteins and GBPs have been shown to restrict replication of viruses ( 3). Stimulation of innate immune cells, such as macrophages, by IFN-γ up-regulates almost 2,000 effector genes encoding various IFN-γ–inducible proteins, including immunity-related GTPases such as the MX proteins, p47 immunity-related GTPases (IRGs), and p65 guanylate-binding proteins (GBPs) ( 2). IFN-γ is an important T-helper 1 (Th1) cytokine that inhibits the survival and growth of a wide range of intracellular pathogens, such as viruses, bacteria, and parasites ( 1). gondii by negatively regulating the Gbp2–Irga6 axis of IFN-γ–dependent cell-autonomous immunity. Taken together, our results suggest that RabGDIα inhibits host defense against T. Notably, Gbp2 positively controlled Irga6 recruitment that was inhibited by direct and specific interactions of RabGDIα with Gbp2 through the lipid-binding pocket.
gondii-forming parasitophorous vacuoles in RabGDIα-deficient cells. Among members of IRGs and GBPs important for the parasite clearance, Irga6 and Gbp2 alone were more frequently recruited to T. gondii, RabGDIα-deficient mice exhibited a decreased parasite burden in the brain and increased resistance in the chronic phase than did control mice. Furthermore, upon a high dose of infection by T. Conversely, RabGDIα deletion in macrophages and fibroblasts enhanced the IFN-γ–induced clearance of T. Overexpression of RabGDIα, but not of RabGDIβ, impaired IFN-γ–dependent reduction of T. Here, we show that Rab GDP dissociation inhibitor α (RabGDIα), originally identified as a Rab small GTPase inhibitor, is a negative regulator of IFN-γ–inducible GTPases in cell-autonomous immunity to the intracellular pathogen Toxoplasma gondii. Although the positive regulation for the proper recruitment of IRGs and GBPs to the vacuoles has been elucidated, the suppressive mechanism is unclear. IFN-γ–inducible GTPases, such as p47 immunity-related GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), are recruited to pathogen-containing vacuoles, which is important for disruption of the vacuoles, culminating in the cell-autonomous clearance. IFN-γ orchestrates cell-autonomous host defense against various intracellular vacuolar pathogens.
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