RabGDIα is a negative regulator of interferon-γ-inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii

Jun Ohshima, Miwa Sasai, Jianfa Liu, Kazuo Yamashita, Ji Su Ma, Youngae Lee, Hironori Bando, Jonathan C. Howard, Shigeyuki Ebisu, Mikako Hayashi, Kiyoshi Takeda, Daron M. Standley, Eva Maria Frickel, Masahiro Yamamoto

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E4581-E4590
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
DOIs
Publication statusPublished - 2015 Aug 18
Externally publishedYes

Keywords

  • Cell-autonomous immunity
  • IFN-γ-inducible GTPase
  • Negative regulation
  • Toxoplasma gondii

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'RabGDIα is a negative regulator of interferon-γ-inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii'. Together they form a unique fingerprint.

  • Cite this

    Ohshima, J., Sasai, M., Liu, J., Yamashita, K., Ma, J. S., Lee, Y., Bando, H., Howard, J. C., Ebisu, S., Hayashi, M., Takeda, K., Standley, D. M., Frickel, E. M., & Yamamoto, M. (2015). RabGDIα is a negative regulator of interferon-γ-inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii. Proceedings of the National Academy of Sciences of the United States of America, 112(33), E4581-E4590. https://doi.org/10.1073/pnas.1510031112