title: RabGDIα is a negative regulator of interferon-γ-inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii.
abstract: IFN-γ orchestrates cell-autonomous host defense against various intracellular vacuolar pathogens. 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. 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 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. Overexpression of RabGDIα, but not of RabGDIβ, impaired IFN-γ-dependent reduction of T. gondii numbers. Conversely, RabGDIα deletion in macrophages and fibroblasts enhanced the IFN-γ-induced clearance of T. gondii. Furthermore, upon a high dose of infection by T. gondii, RabGDIα-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 RabGDIα-deficient cells. Notably, Gbp2 positively controlled Irga6 recruitment that was inhibited by direct and specific interactions of RabGDIα with Gbp2 through the lipid-binding pocket. Taken together, our results suggest that RabGDIα inhibits host defense against T. gondii by negatively regulating the Gbp2-Irga6 axis of IFN-γ-dependent cell-autonomous immunity.
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan 5650871; Laboratory of Immunoparasitology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan 5650871; Department of Restorative Dentistry and Endodontology, Graduate School of Dentistry, Osaka University, Osaka, Japan 5650871;
authors.forename: Jun
authors.initials: J
authors.lastname: Ohshima
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan 5650871; Laboratory of Immunoparasitology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan 5650871;
authors.forename: Miwa
authors.initials: M
authors.lastname: Sasai
authors.affiliation: Department of Pathology and Pathogenic Biology, Medical College of Ningbo University, Ningbo City, China 315211;
authors.forename: Jianfa
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of System Immunology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan 5650871;
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Laboratory of Immunoparasitology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan 5650871;
authors.forename: Ji Su
authors.initials: JS
authors.lastname: Ma
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan 5650871;
authors.forename: Youngae
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan 5650871;
authors.forename: Hironori
authors.initials: H
authors.lastname: Bando
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany 50674;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Howard
authors.affiliation: Department of Restorative Dentistry and Endodontology, Graduate School of Dentistry, Osaka University, Osaka, Japan 5650871;
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Ebisu
authors.affiliation: Department of Restorative Dentistry and Endodontology, Graduate School of Dentistry, Osaka University, Osaka, Japan 5650871;
authors.forename: Mikako
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Laboratory of Mucosal Immunology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan 5650871; Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan 5650871;
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Laboratory of System Immunology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan 5650871;
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.affiliation: Division of Parasitology, Medical Research Council National Institute of Medical Research, London, United Kingdom SN2 1FL; The Francis Crick Institute, London, United Kingdom NW7 1AA.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Frickel
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan 5650871; Laboratory of Immunoparasitology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan 5650871; myamamoto@biken.osaka-u.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D014122:Toxoplasma / Q000472:pathogenicity*; D014123:Toxoplasmosis / Q000276:immunology*; D014709:Vero Cells
chemical_list: D017931:DNA Primers; C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors; D008055:Lipids; D007371:Interferon-gamma; D020558:GTP Phosphohydrolases
keywords: IFN-γ–inducible GTPase; Toxoplasma gondii; cell-autonomous immunity; negative regulation