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Extensive Characterization of IFN-Induced GTPases mGBP1 to mGBP10 Involved in Host Defense¹

Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Dusseldorf, Germany

IFN- orchestrates a potent antimicrobial host response. However, the underlying molecular basis for this immunological defense system is largely unknown. In a systematic approach to identify IFN--regulated host effector molecules, a notable number of transcripts with consensus GTP-binding motives were obtained. Further extensive transcriptome and genome analyses identified five novel family members of murine guanylate-binding proteins (mGBPs) now designated mGBP6, 7, 8, 9, and 10. Moreover, in this study, all 10 mGBP members (mGBP1–10) were extensively characterized. mGBPs are selectively up-regulated in vitro by a set of proinflammatory cytokines and TLR agonists as well as in vivo after Listeria monocytogenes and Toxoplasma gondii infection. After IFN- stimulation, mGBP1, 2, 3, 6, 7, and 9 are associated with intracellular Toxoplasma parasites and, interestingly, virulent Toxoplasma interfere with mGBP recruitment. Taken together, mGBPs comprise an important set of host defense molecules.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants PF259/3-3, FOR729, and Leibniz (to K.P.) and GRK1045/1 (to S.B. and K.P.) from Deutsche Forschungsgemeinschaft and MUGEN (to K.P.).

² D.D., C.K., and C.B.-G. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Sandra Beer or Dr. Klaus Pfeffer, Institute of Medical Microbiology and Hospital Hygiene, Universitaetsstrasse 1, Geb. 22.21, Dusseldorf, Germany. E-mail addresses: sandra.beer{at}uni-duesseldorf.de or klaus.pfeffer{at}uni-duesseldorf.de

⁴ Abbreviations used in this paper: GBP, guanylate-binding protein; IRG, immunity-related GTPase; PV, parasitophorous vacuole; VSV, vesicular stomatitis virus; IRG, immunity-related GTPase; hGBP, human GBP; mGBP, murine GBP; DAPI, 4',6-diamidino-2-phenylindole; iNOS, inducible NO synthase; MEF, murine embryonic fibroblast.

⁵ The online version of this article contains supplemental material.