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Extensive Characterization of IFN-Induced Gtpases Mgbp1 to Mgbp10 Involved in Host Defense

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Extensive Characterization of IFN-Induced Gtpases Mgbp1 to Mgbp10 Involved in Host Defense Extensive Characterization of IFN-Induced GTPases mGBP1 to mGBP10 Involved in Host Defense This information is current as Daniel Degrandi, Carolin Konermann, Cornelia of October 1, 2021. Beuter-Gunia, Alexandra Kresse, Jan Würthner, Stefanie Kurig, Sandra Beer and Klaus Pfeffer J Immunol 2007; 179:7729-7740; ; doi: 10.4049/jimmunol.179.11.7729 http://www.jimmunol.org/content/179/11/7729 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2008/03/10/179.11.7729.DC1 Material http://www.jimmunol.org/ References This article cites 56 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/179/11/7729.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Extensive Characterization of IFN-Induced GTPases mGBP1 to mGBP10 Involved in Host Defense1 Daniel Degrandi,2 Carolin Konermann,2 Cornelia Beuter-Gunia,2 Alexandra Kresse, Jan Wu¨rthner, Stefanie Kurig, Sandra Beer,3 and Klaus Pfeffer3 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, Downloaded from virulent Toxoplasma interfere with mGBP recruitment. Taken together, mGBPs comprise an important set of host defense molecules. The Journal of Immunology, 2007, 179: 7729–7740. nterferons and TNF factors are essential for control of intra- intracellular pathogens, such as Listeria monocytogenes and Tox- cellular pathogens (1–3). Moreover IFN-␥ has been shown to oplasma gondii in mice (6, 9). Although IRGs exist in several be important for survival in polymicrobial sepsis (4). IFNs mammalian species, the gene family appears to be degenerated in I http://www.jimmunol.org/ regulate the expression of several hundred genes, including three humans (10). families of GTPases: Mx proteins, p47 GTPases, and p65 guany- In contrast, the 65-kDa GBPs are highly conserved throughout late-binding proteins (GBPs)4 (5, 6). The p65 GBPs and the im- the vertebrate lineage. After the first description of human GBP1 munity-related GTPases (IRGs), formerly named as p47 GTPases, (hGBP1) (11, 12), closely related genes have been found in mice, are among the most abundantly activated transcripts induced by humans, and several other species (13–18). IFN-␥. Together with type I IFN-induced Mx proteins, IRGs were GBPs have been assigned to the superfamily of dynamin-related described as playing important roles during pathogen infections GTP-binding proteins (19). Although diverse in their primary se- (7). Mx proteins have been shown to possess a potent antiviral quences, dynamin-related GTP-binding proteins have common activity against a wide range of RNA viruses, e.g., influenza and structural features comprising a large GTP-binding domain, a mid- by guest on October 1, 2021 vesicular stomatitis virus (VSV). Recent studies have attributed dle domain, and a GTPase effector domain as well as the common this effect to direct interaction of the protein with viral particles, biochemical property of oligomerization-dependent GTPase activ- ␥ thereby inhibiting viral replication (8). The IFN- induced IRGs ity (19). have been the subject of extensive studies in recent years (6, 9). Despite that 65-kDa GBPs have been known for Ͼ20 years, most Currently 23 IRG genes are known in mice (10). Through the aspects of their functions remain enigmatic. Recent studies have investigation of gene-deficient mouse strains, members of the shown that hGBP1 and murine GBP2 (mGBP2) are involved in cell IRGs, such as Irgm1 (LRG-47), Irgd (IRG-47), and Irgm3 (IGTP), growth regulation. Overexpression of mGBP2 promotes cell prolifer- have been established as essential proteins during infection with ation in NIH 3T3 fibroblasts (20), whereas retroviral expression of hGBP1 inhibits proliferation of human endothelial cells (21). Al- though these findings seem contradictory at first, the effects of Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Dusseldorf, Germany mGBP2 and hGBP1 mirror the respective proliferative activities of IFN-␥ on these cell lines. hGBP1 also has been shown to negatively Received for publication June 27, 2007. Accepted for publication August 22, 2007. regulate expression of matrix metalloproteinase 1 in endothelial cells, 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 leading to reduced invasive capabilities of the cells into collagen I with 18 U.S.C. Section 1734 solely to indicate this fact. matrices (22). Additionally, hGBP1 expression has been associated 1 This work was supported by Grants PF259/3-3, FOR729, and Leibniz (to K.P.) and with paclitaxel resistance in ovarian cancer cell lines (23). GRK1045/1 (to S.B. and K.P.) from Deutsche Forschungsgemeinschaft and MUGEN Furthermore, with respect to immune function, hGBP1 and (to K.P.). mGBP2 have been shown to mediate antiviral activities in HeLa 2 D.D., C.K., and C.B.-G. contributed equally to this study. cells and NIH 3T3 fibroblasts, respectively, after infection with 3 Address correspondence and reprint requests to Dr. Sandra Beer or Dr. Klaus Pfef- fer, Institute of Medical Microbiology and Hospital Hygiene, Universitaetsstrasse 1, VSV or encephalomyocarditis virus (24, 25). However, this anti- Geb. 22.21, Dusseldorf, Germany. E-mail addresses: [email protected] viral activity was significantly lower than that measured for Mx or [email protected] proteins. The viral growth inhibition by mGBP2 was dependent on 4 Abbreviations used in this paper: GBP, guanylate-binding protein; IRG, immunity- GTP binding for encephalomyocarditis virus but not for VSV, sug- related GTPase; PV, parasitophorous vacuole; VSV, vesicular stomatitis virus; IRG, immunity-related GTPase; hGBP, human GBP; mGBP, murine GBP; DAPI, 4Ј,6- gesting different effector mechanisms of the protein depending on diamidino-2-phenylindole; iNOS, inducible NO synthase; MEF, murine embryonic the type of virus. However, the biological functions of GBPs in fibroblast. host defense against bacterial and protozoan infections have been Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 elusive up to now. www.jimmunol.org 7730 CHARACTERIZATION OF mGBP1 TO mGBP10 In an effort to screen for IFN-␥-initiated antimicrobial mecha- For stimulation experiments, the following reagents were used: 10 ng/ml nisms in immune cells, five cDNAs were identified that encode recombinant mouse IFN-␤ (PBL Biomedical Laboratories), 10 ng/ml re- ␥ novel members of the 65-kDa mGBP family, extending its number combinant mouse IFN- (R&D Systems), 10 ng/ml recombinant murine IL-1␤ (R&D Systems), 10 ng/ml recombinant murine IL-2 (R&D Sys- to 10 highly homologous genes. All mGBPs were the subject of tems), 10 ng/ml recombinant murine TNF-␣ (R&D Systems), 1 ␮g/ml extensive mRNA and protein expression analyses demonstrating a lipoteichoic acid (derived from L. monocytogenes; provided by T. Hartung, strong induction in vitro under proinflammatory conditions and in Konstanz, Germany), 100 ng/ml LPS E. coli 055:B5 (Sigma-Aldrich), 1 vivo after infection of mice with L. monocytogenes or T. gondii. ␮M CpG1668 (TIB MOLBIOL), and 1 ␮g/ml poly(I:C) (Sigma-Aldrich). At the indicated time points, cells were harvested for preparation of RNA. Additionally, an enclosure of intracellular T. gondii by distinct Unstimulated cells served as control. mGBP family members could be shown. Interestingly, highly virulent T. gondii were able to interfere with the enclosure by mGBPs. Taken Real-time RT-PCR analyses together, this is the first report that indicates a role for mGBPs in host Total RNA from cells or tissues was isolated using TRIzol reagent (In- defense in bacterial and protozoan infections. vitrogen Life Technologies) according to the manufacturer’s protocol. First-strand cDNA synthesis was performed using 1 ␮g of total RNA with Materials
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