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Balance of Irgm protein activities determines IFN‐γ‐induced host defense
Author(s) -
Henry Stanley C.,
Daniell Xiaoju G.,
Burroughs Ashley R.,
Indaram Maanasa,
Howell David N.,
Coers Jörn,
Starnbach Michael N.,
Hunn Julia P.,
Howard Jonathan C.,
Feng Carl G.,
Sher Alan,
Taylor Gregory A.
Publication year - 2009
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1008599
Subject(s) - biology , microbiology and biotechnology , intracellular parasite , context (archaeology) , gtpase , intracellular , motility , phenotype , immunity , genetics , immune system , gene , paleontology
The immunity‐related GTPases (IRG), also known as p47 GTPases, are a family of proteins that are tightly regulated by IFNs at the transcriptional level and serve as key mediators of IFN‐regulated resistance to intracellular bacteria and protozoa. Among the IRG proteins, loss of Irgm1 has the most profound impact on IFN‐γ‐induced host resistance at the physiological level. Surprisingly, the losses of host resistance seen in the absence of Irgm1 are sometimes more striking than those seen in the absence of IFN‐γ. In the current work, we address the underlying mechanism. We find that in several contexts, another protein in the IRG family, Irgm3, functions to counter the effects of Irgm1. By creating mice that lack Irgm1 and Irgm3, we show that several phenotypes important to host resistance that are caused by Irgm1 deficiency are reversed by coincident Irgm3 deficiency; these include resistance to Salmonella typhimurium in vivo, the ability to affect IFN‐γ‐induced Salmonella killing in isolated macrophages, and the ability to regulate macrophage adhesion and motility in vitro. Other phenotypes that are caused by Irgm1 deficiency, including susceptibility to Toxoplasma gondii and the regulation of GKS IRG protein expression and localization, are not reversed but exacerbated when Irgm3 is also absent. These data suggest that members of the Irgm subfamily within the larger IRG family possess activities that can be opposing or cooperative depending on the context, and it is the balance of these activities that is pivotal in mediating IFN‐γ‐regulated host resistance.