Universität zu Köln

Ohshima, Jun, Sasai, Miwa ORCID: 0000-0001-6440-3958, Liu, Jianfa, Yamashita, Kazuo, Ma, Ji Su, Lee, Youngae, Bando, Hironori, Howard, Jonathan C., Ebisu, Shigeyuki, Hayashi, Mikako, Takeda, Kiyoshi, Standley, Daron M., Frickeli, Eva-Maria and Yamamoto, Masahiro (2015). RabGDI alpha 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). S. E4581 - 10. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

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 (RabGDI alpha), 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 RabGDI alpha, but not of RabGDI beta, impaired IFN-gamma-dependent reduction of T. gondii numbers. Conversely, RabGDI alpha deletion in macrophages and fibroblasts enhanced the IFN-gamma-induced clearance of T. gondii. Furthermore, upon a high dose of infection by T. gondii, RabGDI alpha-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 RabGDI alpha-deficient cells. Notably, Gbp2 positively controlled Irga6 recruitment that was inhibited by direct and specific interactions of RabGDI alpha with Gbp2 through the lipid-binding pocket. Taken together, our results suggest that RabGDI alpha inhibits host defense against T. gondii by negatively regulating the Gbp2-Irga6 axis of IFN-gamma-dependent cell-autonomous immunity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ohshima, Jun UNSPECIFIED UNSPECIFIED UNSPECIFIED Sasai, Miwa UNSPECIFIED orcid.org/0000-0001-6440-3958 UNSPECIFIED Liu, Jianfa UNSPECIFIED UNSPECIFIED UNSPECIFIED Yamashita, Kazuo UNSPECIFIED UNSPECIFIED UNSPECIFIED Ma, Ji Su UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Youngae UNSPECIFIED UNSPECIFIED UNSPECIFIED Bando, Hironori UNSPECIFIED UNSPECIFIED UNSPECIFIED Howard, Jonathan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ebisu, Shigeyuki UNSPECIFIED UNSPECIFIED UNSPECIFIED Hayashi, Mikako UNSPECIFIED UNSPECIFIED UNSPECIFIED Takeda, Kiyoshi UNSPECIFIED UNSPECIFIED UNSPECIFIED Standley, Daron M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frickeli, Eva-Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Yamamoto, Masahiro UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-396338
DOI:	10.1073/pnas.1510031112
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	112
Number:	33
Page Range:	S. E4581 - 10
Date:	2015
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GDP-DISSOCIATION INHIBITOR; GUANYLATE-BINDING-PROTEIN; MOLECULAR-CLONING; HOST-RESISTANCE; MEMBRANE; DISRUPTION; AUTOPHAGY; RECOGNITION; RESPONSES; VACUOLAR Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39633