Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Immunity-Related GTPases (IRG)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_170

Synonyms

Historical Background

The IRGs are a family of large GTP-binding proteins that play roles in immune and inflammatory processes (Pilla-Moffett et al. 2016; Kim et al. 2012; Hunn et al. 2011). They are closely related to three other families of GTP-binding proteins: the Mx proteins, guanylate-binding proteins (GBPs), and very large IFN-inducible GTPases. The IRGs were discovered in the 1990s by scientists who were conducting screens for mouse genes that were upregulated by IFN-γ and/or lipopolysaccharide (LPS). Those IRGs were named and described piecemeal, but later, a standardized nomenclature (Bekpen et al. 2005) placed the IRGs into subfamilies based on amino acid homology within the GTP-binding regions. Most subfamilies contain a canonical GKS sequence within the G1 motif in the GTP-binding region (IRGA, IRGB, IRGC, IRGD, IRGE, and IRGF), while a noncanonical GMS sequence is found only in the IRGM proteins, which is thought to lead to the distinct functional roles of this subfamily. The IRG genes have been found across vertebrates, yet their distribution is uneven with C57Bl/6 mice, for instance, having 23 members and humans only two. This expansion of the IRGs in some species may reflect relatively recent evolutionary events to combat unique pressures from endemic pathogens. Indeed, knock-out mouse studies have established that IRGs are important for immunity against a variety of protozoan and bacterial pathogens. More recently, human GWAS studies have associated variants in the human IRGM gene with Crohn’s disease, mycobacterial resistance, and sepsis outcomes.

Gene Expression

Expression of most mouse IRG genes is highly induced by type I and type II interferons (IFN), as a consequence of multiple interferon-stimulated response elements (ISRE) and γ-activated sequences (GAS) found in the promoters of the genes (Bekpen et al. 2005). It is notable, however, that the positions of these elements vary from gene to gene in the mouse, implying that there has been evolutionary pressure to maintain IFN-regulated expression. The transcriptional response to IFNγ is rapid; for Irgm3, for instance, mRNA accumulates within 1 h of stimulation, reaching maximal levels within 3 h and having a half-life of about 4.5 h (Taylor et al. 1996). Irgm3 protein accumulates within 3 h of induction and reaches maximal levels within 8 h that do not decrease in the continued presence of IFN-. Expression of IRGs has been noted in a wide variety of tissues and cell types, both hematopoietic and nonhematopoietic. Expression of some mouse IRGs (Sorace et al. 1995), and of human IRGM (Chauhan et al. 2015), is induced by LPS. However, a variety of other cytokines do not induce expression of IFN-regulated IRG genes, underscoring the specificity of IFN and LPS in controlling expression (Sorace et al. 1995).

Biochemical Properties

IRGs are members of the dynamin protein superfamily (Martens and Howard 2006). Although IRGs share little sequence homology with the dynamins outside of the GTP-binding region, they do share the GTPase function, a high affinity for lipid membranes, the ability to assemble into dimers and oligomers, and the ability to mechanically alter membranes. As a consequence of these biochemical properties, the IRGs are thought to be involved in membrane remodeling and trafficking events within cells. The related guanylate-binding proteins (GBP) and the Mx proteins are similarly related to the dynamins (Martens and Howard 2006).

The abilities to bind and hydrolyze GTP to GDP have been confirmed for Irgm1, Irgm3, and Irga6 (Taylor et al. 1997; Uthaiah et al. 2003). Extensive biochemical and structural studies of Irga6 (Uthaiah et al. 2003; Schulte et al. 2016; Ghosh et al. 2004) have served as models that may be representative of the majority of IRG proteins.

IRG proteins are found in many different membrane compartments within the cell depending on the particular IRG, including the endoplasmic reticulum, the Golgi, lysosomes, mitochondria, peroxisomes, and the plasma membrane, with the exact localization pattern varying with the particular IRG (Taylor et al. 1997; Martens et al. 2004; Henry et al. 2014; Haldar et al. 2013). The degree to which the proteins associate with membranes is also variable, ranging from >90% (for the IRGMs) to <10% (e.g., for IRGC) (Martens et al. 2004). Diverse mechanisms are involved in membrane localization including myristoylation, palmitoylation, and amphipathic helices (Martens et al. 2004; Henry et al. 2014). Targeting to most of these membranes does not involve GTP hydrolysis. However, many IRGs relocalize to vacuoles/phagosomes in cells infected with pathogens (most notably Toxoplasma gondii) with GTP hydrolysis triggering protein dimerization on the membrane. IRG complexes that assemble on pathogen-containing vacuoles are heterotypic, and the assembly is cooperative and ordered (Hunn et al. 2008; Khaminets et al. 2010).

Immune Functions

The creation and analysis of mice lacking IRG proteins – Irgm1, Irgm3, Irgd, and Irga6 – have established the prominent role that the GTPases play in innate immunity to multiple intracellular pathogens (Taylor et al. 2000; Collazo et al. 2001; MacMicking et al. 2003; Henry et al. 2007; Al-Zeer et al. 2009; Taylor 2007; Liesenfeld et al. 2011). The clear but distinct phenotypes of the IRG-deficient mouse strains have also emphasized that the genes are nonredundant and of varying importance for immune resistance depending on the pathogen.

IRG proteins are extensively involved in resistance to Toxoplasma gondii in mice, which may have predicated the expansion of the gene family in that species (Gazzinelli et al. 2014). Mice lacking Irgm1 or Irgm3 demonstrate acute susceptibility to this protozoan parasite on par with the susceptibility in IFNγ-deficient mice, underscoring the essential role for the IRGM proteins in IFNγ-induced resistance (Taylor et al. 2000; Collazo et al. 2001). In contrast, Irgd and Irga6-deficient mice demonstrate weak susceptibility that becomes manifest later during the infection (Collazo et al. 2001; Liesenfeld et al. 2011). The role of the IRGs in resistance is tied to their ability to provide cell autonomous resistance to T. gondii: Macrophages or astrocytes that lack IRG proteins demonstrate varying degrees of impaired IFNγ-induced T. gondii killing activity (Butcher et al. 2005; Halonen et al. 2001). Data from several studies have suggested a model in which GKS IRG proteins load onto the T. gondii vacuole, where they drive vesiculation of that vacuole, releasing the parasite into the cytosol of the cell where it is destroyed (Ling et al. 2006; Zhao et al. 2009). GMS IRGM proteins, in contrast, do not load to the same extent on the vacuole; rather, they regulate the GKS proteins, such that in absence of the GMS IRG proteins, the GKS IRG proteins inappropriately activate and form aberrant aggregates, leaving them unavailable to load as efficiently onto T. gondii vacuoles (Hunn et al. 2008). The pivotal function of IRG protein family in eradicating T. gondii is underscored by the fact that virulent strains of the parasite have acquired the ability to phosphorylate IRGs, which prevents their loading onto the parasitophorous vacuole (Fentress et al. 2008; Steinfeldt et al. 2015). IRG-deficient mice also have altered resistance to other parasites including Leishmania major, Trypanosoma cruzi, and Plasmodium berghei (Santiago et al. 2005; de Souza et al. 2003; Murray et al. 2015; Guo et al. 2015), but the underlying mechanism(s) in those cases have not been elucidated and may well be distinct from the vacuole attack mechanism seen with T. gondii.

Irgm1-deficient mice also display increased susceptibility to bacterial pathogens including Listeria monocytogenes, Salmonella typhimurium, Mycobacterium tuberculosis, Mycobacterium avium, and Chlamydia trachomatis (Collazo et al. 2001; MacMicking et al. 2003; Henry et al. 2007; Taylor 2007; Feng et al. 2004; Bernstein-Hanley et al. 2006). Irgm1 is unique among the mouse IRGs in this respect, as other IRG-deficient mice have shown little or no susceptibility to bacteria, with the exception of C. trachomatis (Collazo et al. 2001; Al-Zeer et al. 2009; Coers et al. 2008). Multiple changes in the immune response of Irgm1-deficient mice have been noted that may contribute to susceptibility to bacterial infection; these include decreased bacterial processing/killing in IFN-activated macrophages (MacMicking et al. 2003; Henry et al. 2007; Gutierrez et al. 2004) and decreased T cell responses (Feng et al. 2004, 2008a, b). Both may result from the decreased autophagic functioning (Traver et al. 2011) and/or altered mitochondrial dynamics (Henry et al. 2014) that have been documented in Irgm1-deficient cells. Alterations in these processes may result from a direct role of Irgm1 in autophagy and/or mitochondrial dynamics, or indirectly as a result of the GKS IRG protein aggregates that accumulate in cells deficient in IRGM proteins such as Irgm1 (Maric-Biresev et al. 2016). A role for human IRGM in bacterial resistance has also been suggested by GWAS studies (King et al. 2011; Intemann et al. 2009), as well as by in vitro studies with model bacterial pathogens showing decreased bacterial killing in host cells treated with IRGM siRNA (McCarroll et al. 2008; Singh et al. 2006; Brest et al. 2011; Lapaquette et al. 2010). This role for IRGM in antibacterial immunity is likely also driven by the role(s) it plays in autophagy (Chauhan et al. 2015; Singh et al. 2006) and/or mitochondrial functioning (Singh et al. 2010).

IRGM proteins have been linked to inflammatory disease in two settings: Crohn’s disease and sepsis. In mice, Irgm1-deficiency leads to enhanced intestinal inflammation when mice are exposed to dextran sodium sulfate, a standard chemical inducer of experimental colitis (Wirtz et al. 2007). The mice display increases in both ileal and colonic inflammation, while accompanying the inflammation are enhanced weight loss, colonic shortening, intestinal bleeding, and loss of stool consistency. This syndrome is accompanied by altered autophagic processing of secretory granules in Paneth cells and altered production of defensins and inflammatory cytokines. In humans, multiple IRGM gene variants have been identified that lend susceptibility to Crohn’s Disease (Wellcome Trust Case Consortium 2007; Parkes et al. 2007). These not only increase the risk of developing CD but also increase the severity of disease, including fistulating behavior (Latiano et al. 2009), ileal involvement (Roberts et al. 2008), and the need for surgery (Sehgal et al. 2012). Most of the IRGM variants occur in noncoding regions of the gene and are thought to affect expression rather than protein function. Regarding sepsis, Irgm1-deficient mice display enhanced production of the proinflammatory cytokine, tumor necrosis factor, when exposed to LPS, as well as enhanced mortality to LPS-induced shock (Bafica et al. 2007). GWAS studies in humans have associated IRGM gene variants with poor outcomes in sepsis patients (Kimura et al. 2014). The underlying mechanism(s) have not been determined, but the aforementioned impairments in autophagy may drive overly robust cytokine responses to bacterial products such as LPS.

Summary

Interferons trigger expression of a diverse range of proteins that provide mechanisms of immune resistance to pathogens. The immunity-related GTPases (IRG) are a family of interferon-induced, membrane-binding proteins that mediate membrane remodeling and membrane trafficking events, which enhance immune functions that contribute to eradication of pathogenic protozoa and bacteria. The best characterized of these mechanisms is the IRG-driven vesiculation of the parasitophorous vacuole in T. gondii-infected cells. Other functions of IRG proteins are continuing to emerge, with this research being driven by GWAS studies associating variants of the human IRG gene with Crohn’s disease, mycobacterial resistance, and sepsis outcomes. Current models suggest that these associations relate to the ability of IRGM proteins to modulate the membrane-associated processes of autophagy and/or mitochondrial fission. This, in turn, impacts relevant immune processes including intracellular processing of bacteria in host cells, the generation of secretory granules in intestinal Paneth cells, and inflammatory cytokine production.

References

  1. Al-Zeer MA, Al-Younes HM, Braun PR, Zerrahn J, Meyer TF. IFN-gamma-inducible Irga6 mediates host resistance against Chlamydia trachomatis via autophagy. PLoS One. 2009;4:e4588.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Bafica A, Feng CG, Santiago HC, Aliberti J, Cheever A, Thomas KE, Taylor GA, Vogel SN, Sher A. The IFN-inducible GTPase LRG47 (Irgm1) negatively regulates TLR4-triggered proinflammatory cytokine production and prevents endotoxemia. J Immunol. 2007;179:5514–22.PubMedCrossRefGoogle Scholar
  3. Bekpen C, Hunn JP, Rohde C, Parvanova I, Guethlein L, Dunn DM, Glowalla E, Leptin M, Howard JC. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol. 2005;6:R92.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Bernstein-Hanley I, Coers J, Balsara ZR, Taylor GA, Starnbach MN, Dietrich WF. The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice. Proc Natl Acad Sci USA. 2006;103:14092–7.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, Mari B, Barbry P, Mosnier JF, Hebuterne X, Harel-Bellan A, Mograbi B, Darfeuille-Michaud A, Hofman P. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet. 2011;43:242–5.PubMedCrossRefGoogle Scholar
  6. Butcher BA, Greene RI, Henry SC, Annecharico KL, Weinberg JB, Denkers EY, Sher A, Taylor GA. p47 GTPases regulate Toxoplasma gondii survival in activated macrophages. Infect Immun. 2005;73:3278–86.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Chauhan S, Mandell MA, Deretic V. IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol Cell. 2015;58:507–21.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Coers J, Bernstein-Hanley I, Grotsky D, Parvanova I, Howard JC, Taylor GA, Dietrich WF, Starnbach MN. Chlamydia muridarum evades growth restriction by the IFN-gamma-inducible host resistance factor Irgb10. J Immunol. 2008;180:6237–45.PubMedCrossRefGoogle Scholar
  9. Collazo CM, Yap GS, Sempowski GD, Lusby KC, Tessarollo L, Woude GF, Sher A, Taylor GA. Inactivation of LRG-47 and IRG-47 reveals a family of interferon gamma-inducible genes with essential, pathogen-specific roles in resistance to infection. J Exp Med. 2001;194:181–8.PubMedCrossRefPubMedCentralGoogle Scholar
  10. de Souza AP, Tang B, Tanowitz HB, Factor SM, Shtutin V, Shirani J, Taylor GA, Weiss LM, Jelicks LA. Absence of interferon-gamma-inducible gene IGTP does not significantly alter the development of chagasic cardiomyopathy in mice infected with Trypanosoma cruzi (Brazil strain). J Parasitol. 2003;89:1237–9.PubMedCrossRefGoogle Scholar
  11. Feng CG, Collazo-Custodio CM, Eckhaus M, Hieny S, Belkaid Y, Elkins K, Jankovic D, Taylor GA, Sher A. Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia. J Immunol. 2004;172:1163–8.PubMedCrossRefGoogle Scholar
  12. Feng CG, Weksberg DC, Taylor GA, Sher A, Goodell MA. The p47 GTPase Lrg-47 (Irgm1) links host defense and hematopoietic stem cell proliferation. Cell Stem Cell. 2008a;2:83–9.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Feng CG, Zheng L, Jankovic D, Bafica A, Cannons JL, Watford WT, Chaussabel D, Hieny S, Caspar P, Schwartzberg PL, Lenardo MJ, Sher A. The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon-gamma-induced cell death. Nat Immunol. 2008b;9:1279–87.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Fentress SJ, Behnke MS, Dunay IR, Mashayekhi M, Rommereim LM, Fox BA, Bzik DJ, Taylor GA, Turk BE, Lichti CF, Townsend RR, Qiu W, Hui R, Beatty WL, Sibley LD. Phosphorylation of immunity-related GTPases by a Toxoplasma gondii-secreted kinase promotes macrophage survival and virulence. Cell Host Microbe. 2008;8:484–95.CrossRefGoogle Scholar
  15. Gazzinelli RT, Mendonca-Neto R, Lilue J, Howard J, Sher A. Innate resistance against Toxoplasma gondii: an evolutionary tale of mice, cats, and men. Cell Host Microbe. 2014;15:132–8.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Ghosh A, Uthaiah R, Howard J, Herrmann C, Wolf E. Crystal structure of IIGP1: a paradigm for interferon-inducible p47 resistance GTPases. Mol Cell. 2004;15:727–39.PubMedCrossRefGoogle Scholar
  17. Guo J, McQuillan JA, Yau B, Tullo GS, Long CA, Bertolino P, Roediger B, Weninger W, Taylor GA, Hunt NH, Ball HJ, Mitchell AJ. IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria. Infect Immun. 2015;83:1406–17.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119:753–66.PubMedCrossRefGoogle Scholar
  19. Haldar AK, Saka HA, Piro AS, Dunn JD, Henry SC, Taylor GA, Frickel EM, Valdivia RH, Coers J. IRG and GBP host resistance factors target aberrant, “non-self” vacuoles characterized by the missing of “self” IRGM proteins. PLoS Pathog. 2013;9:e1003414.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Halonen SK, Taylor GA, Weiss LM. Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP. Infect Immun. 2001;69:5573–6.PubMedCrossRefPubMedCentralGoogle Scholar
  21. Henry SC, Daniell X, Indaram M, Whitesides JF, Sempowski GD, Howell D, Oliver T, Taylor GA. Impaired macrophage function underscores susceptibility to Salmonella in mice lacking Irgm1 (LRG-47). J Immunol. 2007;179:6963–72.PubMedCrossRefGoogle Scholar
  22. Henry SC, Schmidt EA, Fessler MB, Taylor GA. Palmitoylation of the immunity related GTPase, Irgm1: impact on membrane localization and ability to promote mitochondrial fission. PLoS One. 2014;9:e95021.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Hunn JP, Koenen-Waisman S, Papic N, Schroeder N, Pawlowski N, Lange R, Kaiser F, Zerrahn J, Martens S, Howard JC. Regulatory interactions between IRG resistance GTPases in the cellular response to Toxoplasma gondii. EMBO J. 2008;27:2495–509.PubMedCrossRefPubMedCentralGoogle Scholar
  24. Hunn JP, Feng CG, Sher A, Howard JC. The immunity-related GTPases in mammals: a fast-evolving cell-autonomous resistance system against intracellular pathogens. Mamm Genome. 2011;22:43–54.PubMedCrossRefGoogle Scholar
  25. Intemann CD, Thye T, Niemann S, Browne EN, Amanua Chinbuah M, Enimil A, Gyapong J, Osei I, Owusu-Dabo E, Helm S, Rusch-Gerdes S, Horstmann RD, Meyer CG. Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog. 2009;5:e1000577.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Khaminets A, Hunn JP, Konen-Waisman S, Zhao YO, Preukschat D, Coers J, Boyle JP, Ong YC, Boothroyd JC, Reichmann G, Howard JC. Coordinated loading of IRG resistance GTPases on to the Toxoplasma gondii parasitophorous vacuole. Cell Microbiol. 2010;12:939–61.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Kim BH, Shenoy AR, Kumar P, Bradfield CJ, MacMicking JD. IFN-inducible GTPases in host cell defense. Cell Host Microbe. 2012;12:432–44.PubMedCrossRefPubMedCentralGoogle Scholar
  28. Kimura T, Watanabe E, Sakamoto T, Takasu O, Ikeda T, Ikeda K, Kotani J, Kitamura N, Sadahiro T, Tateishi Y, Shinozaki K, Oda S. Autophagy-related IRGM polymorphism is associated with mortality of patients with severe sepsis. PLoS One. 2014;9:e91522.PubMedCrossRefPubMedCentralGoogle Scholar
  29. King KY, Lew JD, Ha NP, Lin JS, Ma X, Graviss EA, Goodell MA. Polymorphic allele of human IRGM1 is associated with susceptibility to tuberculosis in African Americans. PLoS One. 2011;6:e16317.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Lapaquette P, Glasser AL, Huett A, Xavier RJ, Darfeuille-Michaud A. Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol. 2010;12:99–113.PubMedCrossRefGoogle Scholar
  31. Latiano A, Palmieri O, Cucchiara S, Castro M, D’Inca R, Guariso G, Dallapiccola B, Valvano MR, Latiano T, Andriulli A, Annese V. Polymorphism of the IRGM gene might predispose to fistulizing behavior in Crohn’s disease. Am J Gastroenterol. 2009;104:110–6.PubMedCrossRefGoogle Scholar
  32. Liesenfeld O, Parvanova I, Zerrahn J, Han SJ, Heinrich F, Munoz M, Kaiser F, Aebischer T, Buch T, Waisman A, Reichmann G, Utermohlen O, von Stebut E, von Loewenich FD, Bogdan C, Specht S, Saeftel M, Hoerauf A, Mota MM, Konen-Waisman S, Kaufmann SH, Howard JC. The IFN-gamma-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens. PLoS One. 2011;6:e20568.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Ling YM, Shaw MH, Ayala C, Coppens I, Taylor GA, Ferguson DJ, Yap GS. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J Exp Med. 2006;203:2063–71.PubMedCrossRefPubMedCentralGoogle Scholar
  34. MacMicking JD, Taylor GA, McKinney JD. Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science. 2003;302:654–9.PubMedCrossRefGoogle Scholar
  35. Maric-Biresev J, Hunn JP, Krut O, Helms JB, Martens S, Howard JC. Loss of the interferon-gamma-inducible regulatory immunity-related GTPase (IRG), Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient mice to infection. BMC Biol. 2016;14:33.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Martens S, Howard J. The interferon-inducible GTPases. Annu Rev Cell Dev Biol. 2006;22:559–89.PubMedCrossRefGoogle Scholar
  37. Martens S, Sabel K, Lange R, Uthaiah R, Wolf E, Howard JC. Mechanisms regulating the positioning of mouse p47 resistance GTPases LRG-47 and IIGP1 on cellular membranes: retargeting to plasma membrane induced by phagocytosis. J Immunol. 2004;173:2594–606.PubMedCrossRefGoogle Scholar
  38. McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P, Zody MC, Hall JL, Brant SR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Rioux JD, Altshuler D, Daly MJ, Xavier RJ. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet. 2008;40:1107–12.PubMedCrossRefPubMedCentralGoogle Scholar
  39. Murray HW, Mitchell-Flack M, Taylor GA, Ma X. IFN-gamma-induced macrophage antileishmanial mechanisms in mice: A role for immunity-related GTPases, Irgm1 and Irgm3, in Leishmania donovani infection in the liver. Exp Parasitol. 2015;157:103–9.PubMedCrossRefPubMedCentralGoogle Scholar
  40. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D, Drummond H, Lees CW, Khawaja SA, Bagnall R, Burke DA, Todhunter CE, Ahmad T, Onnie CM, McArdle W, Strachan D, Bethel G, Bryan C, Lewis CM, Deloukas P, Forbes A, Sanderson J, Jewell DP, Satsangi J, Mansfield JC, Cardon L, Mathew CG. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007;39:830–2.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Pilla-Moffett D, Barber MF, Taylor GA, Coers J. Interferon-inducible GTPases in host resistance, inflammation and disease. J Mol Biol. 2016;428:3495–513.Google Scholar
  42. Roberts RL, Hollis-Moffatt JE, Gearry RB, Kennedy MA, Barclay ML, Merriman TR. Confirmation of association of IRGM and NCF4 with ileal Crohn’s disease in a population-based cohort. Genes Immun. 2008;9:561–5.PubMedCrossRefGoogle Scholar
  43. Santiago HC, Feng CG, Bafica A, Roffe E, Arantes RM, Cheever A, Taylor G, Vierira LQ, Aliberti J, Gazzinelli RT, Sher A. Mice deficient in LRG-47 display enhanced susceptibility to Trypanosoma cruzi infection associated with defective hemopoiesis and intracellular control of parasite growth. J Immunol. 2005;175:8165–72.PubMedCrossRefGoogle Scholar
  44. Schulte K, Pawlowski N, Faelber K, Frohlich C, Howard J, Daumke O. The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion. BMC Biol. 2016;14:14.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Sehgal R, Berg A, Polinski JI, Hegarty JP, Lin Z, McKenna KJ, Stewart DB, Poritz LS, Koltun WA. Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohn’s disease. Dis Colon Rectum. 2012;55:115–21.PubMedCrossRefGoogle Scholar
  46. Singh SB, Davis AS, Taylor GA, Deretic V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science. 2006;313:1438–41.PubMedCrossRefGoogle Scholar
  47. Singh SB, Ornatowski W, Vergne I, Naylor J, Delgado M, Roberts E, Ponpuak M, Master S, Pilli M, White E, Komatsu M, Deretic V. Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol. 2010;12:1154–65.PubMedCrossRefPubMedCentralGoogle Scholar
  48. Sorace JM, Johnson RJ, Howard DL, Drysdale BE. Identification of an endotoxin and IFN-inducible cDNA: possible identification of a novel protein family. J Leukoc Biol. 1995;58:477–84.PubMedCrossRefGoogle Scholar
  49. Steinfeldt T, Konen-Waisman S, Tong L, Pawlowski N, Lamkemeyer T, Sibley LD, Hunn JP, Howard JC. Phosphorylation of mouse immunity-related GTPase (IRG) resistance proteins is an evasion strategy for virulent Toxoplasma gondii. PLoS Biol. 2015;8:e1000576.CrossRefGoogle Scholar
  50. Taylor GA. IRG proteins: key mediators of interferon-regulated host resistance to intracellular pathogens. Cell Microbiol. 2007;9:1099–107.PubMedCrossRefGoogle Scholar
  51. Taylor GA, Jeffers M, Largaespada DA, Jenkins NA, Copeland NG, Woude GF. Identification of a novel GTPase, the inducibly expressed GTPase, that accumulates in response to interferon gamma. J Biol Chem. 1996;271:20399–405.PubMedCrossRefGoogle Scholar
  52. Taylor GA, Stauber R, Rulong S, Hudson E, Pei V, Pavlakis GN, Resau JH, Vande Woude GF. The inducibly expressed GTPase localizes to the endoplasmic reticulum, independently of GTP binding. J Biol Chem. 1997;272:10639–45.PubMedCrossRefGoogle Scholar
  53. Taylor GA, Collazo CM, Yap GS, Nguyen K, Gregorio TA, Taylor LS, Eagleson B, Secrest L, Southon EA, Reid SW, Tessarollo L, Bray M, McVicar DW, Komschlies KL, Young HA, Biron CA, Sher A, Vande Woude GF. Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP. Proc Natl Acad Sci USA. 2000;97:751–5.PubMedCrossRefPubMedCentralGoogle Scholar
  54. Traver MK, Henry SC, Cantillana V, Oliver T, Hunn JP, Howard JC, Beer S, Pfeffer K, Coers J, Taylor GA. Immunity-related GTPase M (IRGM) proteins influence the localization of guanylate-binding protein 2 (GBP2) by modulating macroautophagy. J Biol Chem. 2011;286:30471–80.PubMedCrossRefPubMedCentralGoogle Scholar
  55. Uthaiah RC, Praefcke GJ, Howard JC, Herrmann C. IIGP1, an interferon-gamma-inducible 47-kDa GTPase of the mouse, showing cooperative enzymatic activity and GTP-dependent multimerization. J Biol Chem. 2003;278:29336–43.PubMedCrossRefGoogle Scholar
  56. Wellcome Trust Case Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–78.Google Scholar
  57. Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–6.PubMedCrossRefGoogle Scholar
  58. Zhao YO, Khaminets A, Hunn JP, Howard JC. Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. PLoS Pathog. 2009;5:e1000288.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Departments of Medicine, Molecular Genetics and Microbiology, and ImmunologyDuke University Medical Center; Geriatric Research, Education, and Clinical Center, Durham VA Medical CenterDurhamUSA