Key Points
-
The 47-kDa GTP-binding proteins constitute a family of structurally related genes that are upregulated by stimulation with type I and type II interferons (IFNs). Most of these molecules seem to have GTPase enzyme activity.
-
Mice that are deficient in two of the p47 GTPase family members, Igtp and Lrg47, have been shown to be acutely susceptible to various infections with intracellular protozoa and bacteria that are normally controlled by IFN-dependent host-resistance mechanisms. By contrast, the same animals are resistant to infection with viruses.
-
Whereas Igtp-deficient mice are highly susceptible to several protozoan pathogens, they are resistant to all bacterial infections that have been tested so far. By contrast, Lrg47-deficient animals fail to control both protozoan and bacterial infections.
-
In the case of Mycobacterium tuberculosis, Lrg47 has been shown to affect intracellular survival of the pathogen by regulating phagosome maturation and acidification.
-
Additional studies indicate that Lrg47 and Igtp can regulate lymphocyte dynamics and therefore influence host resistance by controlling the generation of effector T cells.
Abstract
Activation of the innate immune system by interferon-γ(IFN-γ) is crucial for host resistance to infection. IFN-γ induces the expression of a wide range of mediators that undermine the ability of pathogens to survive in host cells, including a newly discovered family of 47-kDa GTPases. Elimination of different p47 GTPases in mice by gene targeting severely cripples IFN-γ-regulated defence against Toxoplasma gondii, Listeria monocytogenes, Mycobacterium spp. and other pathogens. In this article, we review our understanding of the role of p47 GTPases in resistance to intracellular infection and discuss the present evidence concerning their mode of action.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jouanguy, E. et al. A human IFNγR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nature Genet. 21, 370–378 (1999).
Janssen, R. et al. Divergent role for TNF-α in IFN-γ-induced killing of Toxoplasma gondii and Salmonella typhimurium contributes to selective susceptibility of patients with partial IFN-γ receptor 1 deficiency. J. Immunol. 169, 3900–3907 (2002).
Ottenhoff, T. H. et al. Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nature Genet. 32, 97–105 (2002).
Scharton-Kersten, T. M. et al. In the absence of endogenous IFN-γ, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J. Immunol. 157, 4045–4054 (1996). This study defines interferon-γ (IFN-γ) as a crucial factor for host resistance to Toxoplasma gondii.
Dalton, D. K. et al. Multiple defects in immune cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993). References 5 and 6 were the first to describe the marked effects of complete IFN-γ-signalling deficiency caused by gene inactivation on host defence in mice.
Huang, S. et al. Immune response in mice that lack the interferon-γ receptor. Science 259, 1742–1745 (1993).
Orange, J. S., Wang, B., Terhorst, C. & Biron, C. A. Requirement for natural killer cell-produced interferon-γ in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J. Exp. Med. 182, 1045–1056 (1995).
Ehrt, S. et al. Reprogramming the macrophage transcriptome in response to interferon-γ and mycobacterium tuberculosis: signaling roles for nitric oxide sythase-2 and phagosome oxidase. J. Exp. Med. 194, 1123–1140 (2001).
Fruh, K., Karlson, L. & Yang, Y. In γ-Interferon in Antiviral defense (ed. Karupiah, G.) 39 (Springer, Heidelberg, Germany, 1997).
Scharton-Kersten, T. M., Yap, G., Magram, J. & Sher, A. Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J. Exp. Med. 185, 1261–1273 (1997).
MacMicking, J. D. et al. Identification of nitric oxide as a protective locus against tuberculosis. Proc. Natl Acad. Sci. USA 94, 5243–5248 (1997).
Hackam, D. J. et al. Host resistance to intracellular infection: mutation of the natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J. Exp. Med. 188, 351–364 (1998).
Vidal, S. M., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: identification of a candidate gene for Bcg. Cell 73, 469–485 (1993).
Govoni, G. et al. Genomic structure, promoter sequence, and induction of expression of the mouse Nramp1 gene in macrophages. Genomics 27, 9–19 (1995).
Vasquez-Torres, A. & Fang, F. Oxygen-dependent anti-Salmonella activity of macrophages. Trends Microbiol. 9, 29–33 (2001).
Cassatella, M. A. et al. Molecular basis of interferon-γ and lipopolysaccharide enhancement of phagocyte respiratory burst capability. J. Biol. Chem. 265, 20241–20246 (1990).
Saito, K., Markey, S. P. & Heyes, M. P. Chronic effects of γ-interferon on quinolic acid and indoleamine-2,3-dioxygenase in brain of C57Bl/6 mice. Brain Res. 546, 151–154 (1991).
Murray, H. W. et al. Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of γ-interferon-stimulated human macrophages. Infect. Immun. 57, 845–849 (1989).
Cheng, Y. S., Colonno, R. J. & Yin, F. H. Interferon induction of fibroblast proteins with guanylate binding activity. J. Biol. Chem. 258, 7746–7750 (1983).
Cheng, Y. S., Patterson, C. E. & Staeheli, P. Interferon-induced guanylate-binding proteins lack an N(T)KXD consensus motif and bind GMP in addition to GDP and GTP. Mol. Cell. Biol. 11, 4717–4725 (1991).
Boehm, U. et al. Two families of GTPases dominate the cellular response to IFN-γ. J. Immunol. 161, 6715–6723 (1998). This paper describes the cloning of two p47 GTPases, Iigp and Gtpi, and compares the p47 GTPase family to the guanylate-binding protein (GBP) family.
Praefcke, G. J., Geyer, M., Schwemmle, M., Kalibitzer, H. R. & Herrmann, C. Nucleotide-binding characteristics of human guanylate binding protein 1 (GBP1) and identification of the third GTP-binding motif. J. Mol. Biol. 292, 321–332 (1999).
Nguyen, T. T., Hu, Y., Widney, D. P., Mar, R. A. & Smith, J. B. Murine GBP-5, a new member of the murine guanylate-binding protein family, is coordinately regulated with other GBPs in vivo and in vitro. J. Int. Cyt. Res. 22, 899–909 (2002).
Neun, R., Richter, M. F., Staeheli, P. & Scwemmle, M. GTPase properties of the interferon-induced human guanylate-binding protein 2. FEBS Lett. 390, 69–72 (1996).
Scwemmle, M. & Staeheli, P. The interferon-induced 67 kDa guanylate binding protein (hGBP-1) is a GTPase that converts GTP to GMP. J. Biol. Chem. 269, 11299–11305 (1994).
Anderson, S. L., Carton, J. M., Xing, L. & Rubin, B. Y. Interferon-induced guanylate-binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encophalomyocarditis virus. Virology 256, 8–14 (1999).
Gorbacheva, V. Y., Lindner, D., Sen, G. C. & Vestal, D. J. The interferon (IFN)-induced GTPase, mGBP-2. J. Biol. Chem. 277, 6080–6087 (2002).
Prakash, B., Praefcke, G. J. K., Renault, L., Wittinghofer, A. & Herrmann, C. Structure of the human guanylate-binding protein 1 representing a unique class of GTP-binding proteins. Nature 403, 567–571 (2000).
Staeheli, P. & Haller, O. Interferon-induced Mx protein: a mediator of cellular resistance to influenza virus. Interferon 8, 1–23 (1987).
Accola, M. A., Huang, B., Masri, A. A. & McNiven, M. A. The antiviral dynamin family member, MxA, tubulates lipids and localizes to the smooth endoplasmic reticulum. J. Biol. Chem. 277, 21829–21835 (2002).
Melen, K. et al. Human MxB protein, an interferon-γ-inducible GTPase, contains a nuclear targeting signal and is localized in the heterochromatin region beneath the nuclear envelope. J. Biol. Chem. 271, 23478–23486 (1996).
Haller, O., Frese, M. & Kochs, G. Mx proteins: mediators of innate resistance to RNA viruses. Rev. Sci. Tech. 17, 220–230 (1998).
Landis, H. et al. Human MxA protein confers resistance to Semliki forest virus and inhibits the amplification of a Semliki forest virus-based replicon in the absence of viral structural proteins. J. Virol. 72, 1516–1522 (1998).
Chieux, V. et al. Inhibition of coxsackievirus B4 replication in stably transfected cells expressing human MxA protein. Virology 283, 84–92 (2001).
Hefti, H. P. et al. Human MxA protein protects mice lacking functional α/β interferon system against La Crosse virus and other lethal virus infections. J. Virol. 73, 6984–6991 (1999).
Hinshaw. J. E. & Schmid, S. L. Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding. Nature 374, 190–192 (1995).
Sweitzer, S. M. & Hinshaw, J. E. Dynamin undergoes a GTP-dependent conformational change causing vesiculation. Cell 93, 1021–1029 (1998).
Stowell, M. H. B., Marks, B., Wigge, P. & McMahon, H. T. Nucleotide-dependent conformational changes in dynamin: evidence for a mechanochemical molecular spring. Nature Cell Biol. 1, 27–32 (1999).
Haller, O. & Kochs, G. Interferon-induced Mx proteins: dynamin-like GTPases with antiviral activity. Traffic 3, 710–717 (2002).
Taylor, G. A. et al. Identification of a novel GTPase, the inducibly expressed GTPase (IGTP), that accumulates in response to interferon-γ. J. Biol. Chem. 271, 20399–20405 (1996).
Taylor, G. A. et al. The inducibly expressed GTPase (IGTP) localizes to the endoplasmic reticulum independently of GTP binding. J. Biol. Chem. 272, 10639–10645 (1997).
Sorace, J. M., Johnson, R. J., Howard, D. L. & Drysdale, B. E. Identification of an endotoxin and IFN-γ-inducible cDNA: possible identification of a novel protein family. J. Leukoc. Biol. 58, 477–484 (1995).
Gilly, M. & Wall, R. The IRG-47 gene is IFN-γ induced in B cells and encodes a protein with GTP-binding motifs. J. Immunol. 148, 3275–3281 (1992).
Carlow, D. A., Marth, J., Clark-Lewis, I. & Teh, H. -S. Isolation of a gene encoding a developmentally regulated T cell-specific protein with a guanidine nucleotide triphosphate binding motif. J. Immunol. 154, 1724–1734 (1995).
LaFuse, W. P., Brown, D., Castle, L. & Zwilling, B. S. Cloning and characterization of novel cDNA that is IFN-γ-induced in mouse peritoneal macrophages and encodes a GTP-binding protein. J. Leukoc. Biol. 57, 477–483 (1995).
Carlow, D. A., The, S. -J. & Teh, H. Specific antiviral activity demonstrated by TGTP, a member of a new family of interferon-induced GTPases. J. Immunol. 161, 2348–2355 (1998).
Collazo, C. M. et al. The function of γ-interferon-inducible GTP-binding protein IGTP in host resistance to Toxoplasma gondii is Stat1 dependent and requires expression in both hematopoietic and nonhematopoietic cellular compartments. Infect. Immun. 70, 6933–6939 (2002).
Zerrahn, J., Schaible, U. E., Brinkmann, V., Guhlich, U. & Kaufmann, S. H. E. The IFN-inducible golgi- and endoplasmic reticulum associated 47-kDa GTPase IIGP is transiently expressed during listeriosis. J. Immunol. 168, 3428–3436 (2002).
Taylor, G. A. et al. Pathogen specific loss of host resistance in mice lacking the interferon-γ-inducible gene IGTP. Proc. Natl Acad. Sci. USA 97, 751–755 (2000). The first study that describes genetic targeting of a p47 GTPase and its effects on host resistance.
Carlow, D. A., Teh, S. J. & Teh, H. S. Specific antiviral activity demonstrated by TGTP, a member of a new family of interferon-induced GTPases. J. Immunol. 161, 2348–2355 (1998).
Ulthaiah, R. C., Praefcke, G. J. K., Howard, J. C. & Herrmann, C. IIGP1, an interferon-γ inducible 47 kDa GTPase of the mouse, showing cooperative enzymatic activity and GTP-dependent multimerization. J. Biol. Chem. 278, 29336–29343 (2003). A thorough biochemical study of the GTP-binding properties of the p47 GTPase, Iigp, and the first study to indicate that the p47 GTPases might function through oligomerization.
Sibley, L. D. Interactions between Toxoplasma gondii and its mammalian host cells. Semin. Cell Biol. 4, 335–344 (1993).
Sibley, L. D., Weidner, E. & Krahenbuhl, J. L. Phagosome acidification blocked by intracellular Toxoplasma gondii. Nature 315, 416–419 (1985).
Jones, T. C. & Hirsch, J. G. The interaction between Toxoplasma gondii and mammalian cells. J. Exp. Med. 136, 1173–1193 (1972).
Collazo, C. M. et al. Inactivation of LRG-47 and IRG-47 reveals a family of interferon-γ-inducible genes with essential, pathogen-specific roles in resistance to infection. J. Exp. Med. 194, 181–187 (2001). This paper shows gene-specific and pathogen-specific roles in host resistance for the p47 GTPases.
Halonen, S. K., Taylor, G. A. & Weiss, L. M. γ-interferon-induced inhibition of Toxoplasma gondii in astrocytes in mediated by IGTP. Infect. Immun. 69, 5573–5576 (2001).
Andrews, N. W. Living dangerously: how Trypanosoma cruzi uses lysosomes to get inside host cells, and then escapes into the cytoplasm. Biol. Res. 26, 65–67 (1993).
Sacks, D. & Sher, A. Evasion of innate immunity by parasitic protozoa. Nature Immunol. 3, 1041–1047 (2002).
De Souza, A. P. et al. Absence of interferon-γ inducible gene IGTP does not significantly alter the development of chagasic cardiomyopathy in mice infected with Trypanosoma cruzi (Brazil Strain). J. Parasitol. (in the press).
Cossart, P. & Lecuit, M. Interactions of Listeria monocytogenes with mammalian cells during entry and actin-based movement: bacterial factors, cellular ligands and signaling. EMBO J. 17, 3797–3806 (1998).
Tilney, L. G. & Portnoy, D. A. Actin filaments and the growth, movement, and spread of the intracellular bacterial parasite Listeria monocytogenes. J. Cell. Biol. 109, 1597–1608 (1989).
MacMicking, J., Taylor, G. A. & McKinney, J. Immune control of tuberculosis by IFN-γ-inducible LRG-47. Science 302, 654–659 (2003). The authors found that the p47 GTPase, Lrg47, is central in the resistance to Mycobacterium tuberculosis by promoting the maturation of the bacterial phagosome in macrophages.
Feng, C. G. et al. Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia. J. Immunol. 172, 1163–1168 (2004). This report discusses marked effects of Lrg47 deficiency on the T-cell compartment during infection with Mycobacterium avium.
Gomes, M. S., Florido, M., Pais, T. F. & Appelberg, R. Improved clearance of Mycobacterium avium upon disruption of the inducible nitric oxide synthase gene. J. Immunol. 162, 6734–6739 (1999).
Doherty, T. M. & Sher, A. Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium. J. Immunol. 158, 4822–4831 (1997).
Zhang, H. M. et al. Overexpression of interferon-γ-inducible GTPase inhibits coxsackievirus B3-induced apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway and inhibition of viral replication. J. Biol. Chem. 278, 33011–33019 (2003).
Reddehase, M. J., Mutter, W., Munch, K., Buhring, H. J. & Koszinowski, U. H. CD8+ T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J. Virol. 61, 3102–3108 (1987).
Jonjic, S., Mutter, W., Weiland, F., Reddehase, M. J. & Koszinowski, U. H. Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J. Exp. Med. 169, 1199–1212 (1989).
Heise, M. T. & Virgin, H. W. The T cell independent role of IFN-γ and TNF-α in macrophage activation during murine cytomegalovirus and herpes simplex virus infection. J. Virol. 69, 904–909 (1995).
Hengel, H., Lucin, P., Jonjic, S., Ruppert, T. & Koszinowski, U. H. Restoration of cytomegalovirus antigen presentation by γ-interferon combats viral escape. J. Virol. 68, 289–297 (1994).
Meresse, S., Steele-Mortimer, O., Finlay, B. B. & Gorvel, J. -P. The rab7 GTPase controls the maturation of Salmonella typhimurium-containing vacuoles. EMBO J. 18, 4394–4403 (1999).
Alvarez-Dominguez, C., Barbier, A. M., Beron, W., Wandinger-Ness, A. & Stahl, P. D. Phagocytosed live Listeria monocytogenes influences Rab5-regulated in vitro phagosome-endosome fusion. J. Biol. Chem. 271, 13834–13843 (1996).
Scianimanico, S. et al. Impaired recruitment of the small GTPase rab 7 correlates with the inhibition of phagosome maturation by Leishmania donovani promastogotes. Cell. Microbiol. 1, 19–32 (1999).
Alvarez-Dominguez, C. & Stahl, P. D. Inteferon-γ selectively induced rab5a synthesis and processing in mononuclear cells. J. Biol. Chem. 273, 33901–33904 (1998).
Gagnon, E. et al. Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell 110, 119–131 (2002). The authors describe the contribution of the endoplasmic reticulum to the phagosome during its formation.
Nuoffer, C. & Balch, W. E. GTPases: multifunctional molecular switches regulating vesicular trafficking. Annu. Rev. Biochem. 63, 949–990 (1994).
Gibbs, J. B., Marshall, M. S., Scolnick, E. M., Dixon, R. A. F. & Vogel, U. S. Modulation of guanine nucleotides bound to Ras in NIH3T3 cells by oncogenes, growth factors, and GTPase activating protein (GAP). J. Biol. Chem. 265, 20437–20442 (1990).
Dever, T. E., Glynias, J. & Merrick, W. C. GTP-binding domain: three consensus sequence elements with distinct spacing. Proc. Natl Acad. Sci. USA 84, 1814–1818 (1987).
Acknowledgements
We are grateful to Y. Belkaid, G. Yap, J. MacMicking, J. McKinney, D. Sacks, H. Young and C. Collazo for helpful discussions and intellectual contributions to this work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- NITRIC OXIDE SYNTHASE 2
-
(NOS2). The inducible form of nitric oxide synthase — an important enzyme in the production of nitric oxide — which is produced in response to lipopolysaccharide and interferon-γ by macrophages and other cells. NOS2 has a crucial role in host resistance to infection.
- ISOPRENYLATED PROTEINS
-
Proteins that are post-translationally modified by the covalent addition of an isoprenoid lipid moiety (either a farnesyl or geranylgeranyl group) to a cysteine near the carboxyl terminus of the protein, usually in a Cys-Ala-Ala-Xaa motif. This modification often allows association of the protein with a lipid membrane in the cell.
- OLIGOMERIZATION
-
The association of polypeptide monomers to form a multi-subunit protein.
- GENE KNOCKOUT
-
A technique, also referred to as gene targeting, by which a specific gene is inactivated, usually through the disruption, mutation or removal of a portion of the protein-coding segments of the gene.
- PARASITOPHOROUS VACUOLE
-
An intracellular, membrane-bound vacuole that contains a parasite that has infected a host cell. The vacuole is initially formed from host-cell lipid and protein components, but, subsequently, the character of the vacuole is greatly influenced by the parasite that it contains.
- BONE-MARROW CHIMAERAS
-
Animals in which the endogenous immune system has been inactivated and replaced with the immune system from an allogeneic donor. To accomplish this, the haematopoietic cells of the recipient are lethally irradiated, after which the immune system is reconstituted by intravenous injection of bone-marrow cells from the donor.
- PARTIAL CHEMOTHERAPY
-
The use of antimicrobial agents to allow an otherwise susceptible host to survive through a particular period of infection.
- LYSOSOMES
-
Membrane-bound organelles in the cytoplasm of cells that contain a high concentration of hydrolytic enzymes that are responsible for the degradation of macromolecules. The contents of lysosomes are acidic due to the actions of a vacuolar ATPase.
- T HELPER 1/2 (TH1/2) CELLS
-
Two subsets of T helper cells that are defined by the different spectra of cytokines that they secrete, and, consequently, the different biological functions that they carry out. TH1 cells secrete interferon-γ and are involved in cell-mediated functions such as macrophage activation, whereas TH2 cells function as helpers for B-cell activation and antibody production.
- GRANULOMA
-
A mass of inflammatory cells that arises due to the persistence of an antigen or infectious agent in host tissue. The granuloma contains various cells, including lymphocytes, macrophages, giant cells and fibroblasts.
- ENDOSOMES
-
Membrane-bound vesicles in the cytoplasm of cells that are formed by the fusion of small endocytic vesicles that result from endocytosis. A network of endosomes extends from the plasma membrane of the cell to the perinuclear region.
Rights and permissions
About this article
Cite this article
Taylor, G., Feng, C. & Sher, A. p47 GTPases: regulators of immunity to intracellular pathogens. Nat Rev Immunol 4, 100–109 (2004). https://doi.org/10.1038/nri1270
Issue Date:
DOI: https://doi.org/10.1038/nri1270
This article is cited by
-
Histological and transcriptomic analysis of adipose and muscle of dairy calves supplemented with 5-hydroxytryptophan
Scientific Reports (2021)
-
Functional neutralization of anti-IFN-γ autoantibody in patients with nontuberculous mycobacteria infection
Scientific Reports (2019)
-
Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection
Experimental & Molecular Medicine (2019)
-
Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense
Nature Immunology (2017)
-
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion
BMC Biology (2016)