| First Author | Ohshima J | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 33 | Pages | E4581-90 |
| PubMed ID | 26240314 | Mgi Jnum | J:226569 |
| Mgi Id | MGI:5697769 | Doi | 10.1073/pnas.1510031112 |
| Citation | Ohshima J, et al. (2015) RabGDIalpha is a negative regulator of interferon-gamma-inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii. Proc Natl Acad Sci U S A 112(33):E4581-90 |
| abstractText | IFN-gamma orchestrates cell-autonomous host defense against various intracellular vacuolar pathogens. IFN-gamma-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. Although the positive regulation for the proper recruitment of IRGs and GBPs to the vacuoles has been elucidated, the suppressive mechanism is unclear. Here, we show that Rab GDP dissociation inhibitor alpha (RabGDIalpha), originally identified as a Rab small GTPase inhibitor, is a negative regulator of IFN-gamma-inducible GTPases in cell-autonomous immunity to the intracellular pathogen Toxoplasma gondii. Overexpression of RabGDIalpha, but not of RabGDIbeta, impaired IFN-gamma-dependent reduction of T. gondii numbers. Conversely, RabGDIalpha deletion in macrophages and fibroblasts enhanced the IFN-gamma-induced clearance of T. gondii. Furthermore, upon a high dose of infection by T. gondii, RabGDIalpha-deficient mice exhibited a decreased parasite burden in the brain and increased resistance in the chronic phase than did control mice. Among members of IRGs and GBPs important for the parasite clearance, Irga6 and Gbp2 alone were more frequently recruited to T. gondii-forming parasitophorous vacuoles in RabGDIalpha-deficient cells. Notably, Gbp2 positively controlled Irga6 recruitment that was inhibited by direct and specific interactions of RabGDIalpha with Gbp2 through the lipid-binding pocket. Taken together, our results suggest that RabGDIalpha inhibits host defense against T. gondii by negatively regulating the Gbp2-Irga6 axis of IFN-gamma-dependent cell-autonomous immunity. |
