The Emerging Roles of Human Immunity-Related GTPase M (IRGM) Gene

Harish Changotra


Immunity-related GTPase family M (IRGM) protein, discovered for the first time in 1990, belongs to IRG family of proteins and is divided into five subfamilies (IRGA, IRGB, IRGC, IRGD and IRGM). These are responsive to interferon-g and play a pivotal role in immune response to pathogens in mice. Owing to lack of interferon response element in the promoter region, human IRGM does not respond to interferon-g stimulation, which is why it was earlier thought to be non-functional gene. Moreover, evolutionary history suggests that this gene was non-functional for ~25 million years ago. Bioinformatics has been instrumental in elucidating its evolutionary history as well as functions, especially in its interactions with the proteins of autophagy pathway.  Recently, several studies have demonstrated the various functions of IRGM in limiting different pathogens in humans. This review discusses how and various roles played by IRGM unraveled in the recent years.

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MacMicking JD, Taylor GA, McKinney JD. Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science. 2003;302(5645):654-9. Epub 2003/10/25.

Taylor GA, Collazo CM, Yap GS, Nguyen K, Gregorio TA, Taylor LS, et al. Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP. Proceedings of the National Academy ofciences of the United States of America. 2000;97(2):751-5. Epub 2000/01/19.

Taylor GA, Feng CG, Sher A. p47 GTPases: regulators of immunity to intracellular pathogens. Nature reviews Immunology. 2004;4(2):100-9. Epub 2004/03/26.

Taylor GA. IRG proteins: key mediators of interferon-regulated host resistance to intracellular pathogens. Cell Microbiol. 2007;9(5):1099-107. Epub 2007/03/16.

Ghosh A, Uthaiah R, Howard J, Herrmann C, Wolf E. Crystal structure of IIGP1: a paradigm for interferon-inducible p47 resistance GTPases. Molecular cell. 2004;15(5):727-39. Epub 2004/09/08.

Bekpen C, Hunn JP, Rohde C, Parvanova I, Guethlein L, Dunn DM, et al. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome biology. 2005;6(11):R92. Epub 2005/11/10.

Bekpen C, Marques-Bonet T, Alkan C, Antonacci F, Leogrande MB, Ventura M, et al. Death and resurrection of the human IRGM gene. PLoS Genet. 2009;5(3):e1000403. Epub 2009/03/07.

Singh SB, Ornatowski W, Vergne I, Naylor J, Delgado M, Roberts E, et al. Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol. 2010;12(12):1154-65.Epub 2010/11/26.

McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P, et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet. 2008;40(9):1107-12. Epub 2009/01/24.

Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M. Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates. Genome biology. 2010;11(3):R26. Epub 2010/03/10.

Brain O, Cooney R, Simmons A, Jewell D. Functional consequences of mutations in the autophagy genes in the pathogenesis of Crohn's disease. Inflamm Bowel Dis. 2012;18(4):778-81. Epub 2011/08/11.

Yang D, Chen J, Zhang L, Cha Z, Han S, Shi W, et al. Mycobacterium leprae upregulates IRGM expression in monocytes and monocyte-derived macrophages. Inflammation. 2014;37(4):1028-34. Epub 2014/01/29.

Kimura T, Watanabe E, Sakamoto T, Takasu O, Ikeda T, Ikeda K, et al. Autophagy-related IRGM polymorphism is associated with mortality of patients with severe sepsis. PLoS One. 2014;9(3):e91522. Epub 2014/03/15.

Xia F, Li R, Wang C, Yang S, Tian L, Dong H, et al. IRGM1 regulates oxidized LDL uptake by macrophage via actin-dependent receptor internalization during atherosclerosis. Sci Rep. 2013;3:1867. Epub 2013/05/22.

Gregoire IP, Richetta C, Meyniel-Schicklin L, Borel S, Pradezynski F, Diaz O, et al. IRGM is acommon target of RNA viruses that subvert the autophagy network. PLoS Pathog. 2011;7(12):e1002422. Epub 2011/12/17.

Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular selfdigestion. Nature. 2008;451(7182):1069-75. Epub 2008/02/29.

Kelekar A. Autophagy. Annals of the New York Academy of Sciences. 2005;1066:259-71. Epub 2006/03/15.

He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annual review of genetics. 2009;43:67-93. Epub 2009/08/06.

Che N, Li S, Gao T, Zhang Z, Han Y, Zhang X, et al. Identification of a novel IRGM promoter single nucleotide polymorphism associated with tuberculosis. Clin Chim Acta. 2010;411(21-22):1645-9. Epub 2010/06/16.

Kudchodkar SB, Levine B. Viruses and autophagy. Reviews in medical virology. 2009;19(6):359-78. Epub 2009/09/15.

Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27-42. Epub 2008/01/15.

Petkova DS, Viret C, Faure M. IRGM in autophagy and viral infections. Front Immunol. 2012;3:426. Epub 2013/01/22.

Joubert PE, Meiffren G, Gregoire IP, Pontini G, Richetta C, Flacher M, et al. Autophagy induction by the pathogen receptor CD46. Cell Host Microbe. 2009;6(4):354-66. Epub 2009/10/20.

Meiffren G, Joubert PE, Gregoire IP, Codogno P, Rabourdin-Combe C, Faure M. Pathogen recognition by the cell surface receptor CD46 induces autophagy. Autophagy. 2010;6(2):299-300. Epub 2010/01/21.

Borel S, Espert L, Biard-Piechaczyk M. Macroautophagy Regulation during HIV-1 Infection of CD4+ T Cells and Macrophages. Front Immunol. 2012;3:97. Epub 2012/05/16.

Carter CA, Ehrlich LS. Cell biology of HIV-1 infection of macrophages. Annual review of microbiology. 2008;62:425-43. Epub 2008/09/13.

Espert L, Denizot M, Grimaldi M, Robert-Hebmann V, Gay B, Varbanov M, et al. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. The Journal of clinical investigation. 2006;116(8):2161-72. Epub 2006/08/04.

Espert L, Varbanov M, Robert-Hebmann V, Sagnier S, Robbins I, Sanchez F, et al. Differential role of autophagy in CD4 T cells and macrophages during X4 and R5 HIV-1 infection. PLoS One. 2009;4(6):e5787. Epub 2009/06/06.

Blanchet FP, Moris A, Nikolic DS, Lehmann M, Cardinaud S, Stalder R, et al. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity. 2010;32(5):654-69. Epub 2010/05/11.

Kyei GB, Dinkins C, Davis AS, Roberts E, Singh SB, Dong C, et al. Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. The Journal of cell biology. 2009;186(2):255-68. Epub 2009/07/29.

Su WC, Chao TC, Huang YL, Weng SC, Jeng KS, Lai MM. Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. Journal of virology. 2011;85(20):10561-71. Epub 2011/08/13.

Shrivastava S, Bhanja Chowdhury J, Steele R, Ray R, Ray RB. Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. Journal of virology. 2012;86(16):8705-12. Epub 2012/06/08.

Sir D, Chen WL, Choi J, Wakita T, Yen TS, Ou JH. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology. 2008;48(4):1054-61. Epub 2008/08/09.

Mohl BP, Tedbury PR, Griffin S, Harris M. Hepatitis C virus-induced autophagy is independent of the unfolded protein response. Journal of virology. 2012;86(19):10724-32. Epub 2012/07/28.

Dreux M, Gastaminza P, Wieland SF, Chisari FV. The autophagy machinery is required to initiate hepatitis C virus replication. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(33):14046-51. Epub 2009/08/12.

Tanida I, Fukasawa M, Ueno T, Kominami E, Wakita T, Hanada K. Knockdown of autophagy-related gene decreases the production of infectious hepatitis C virus particles. Autophagy. 2009;5(7):937-45. Epub 2009/07/25.

Joubert PE, Werneke S, de la Calle C, Guivel-Benhassine F, Giodini A, Peduto L, et al. Chikungunyainduced cell death is limited by ER and oxidative stress-induced autophagy. Autophagy. 2012;8(8):1261-3. Epub 2012/07/28.

Krejbich-Trotot P, Gay B, Li-Pat-Yuen G, Hoarau JJ, Jaffar-Bandjee MC, Briant L, et al. Chikungunya triggers an autophagic process which promotes viral replication. Virology journal. 2011;8:432. Epub 2011/09/10.

Singh SB, Davis AS, Taylor GA, Deretic V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science. 2006;313(5792):1438-41. Epub 2006/08/05.

Intemann CD, Thye T, Niemann S, Browne EN, Amanua Chinbuah M, Enimil A, et al. Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog. 2009;5(9):e1000577. Epub 2009/09/15.

King KY, Lew JD, Ha NP, Lin JS, Ma X, Graviss EA, et al. Polymorphic allele of human IRGM1 is associated with susceptibility to tuberculosis in African Americans. PLoS One. 2011;6(1):e16317. Epub 2011/02/02.

Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39(5):596-604. Epub 2007/04/17.

Birmingham CL, Smith AC, Bakowski MA, Yoshimori T, Brumell JH. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J Biol Chem. 2006;281(16):11374-83. Epub 2006/02/24.

Huett A, McCarroll SA, Daly MJ, Xavier RJ. On the level: IRGM gene function is all about expression. Autophagy. 2009;5(1):96-9. Epub 2008/11/26.

Podolsky DK. Inflammatory bowel disease. The New England journal of medicine. 2002;347(6):417- 29. Epub 2002/08/09.

Choi AJ, Ryter SW. Autophagy in inflammatory diseases. International journal of cell biology. 2011;2011:732798. Epub 2011/12/23.

Massey DC, Parkes M. Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease. Autophagy. 2007;3(6):649-51. Epub 2007/10/09.

Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40(8):955-62. Epub 2008/07/01.

Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet. 2007;39(7):830-2. Epub 2007/06/08.

Glas J, Seiderer J, Bues S, Stallhofer J, Fries C, Olszak T, et al. IRGM variants and susceptibility to inflammatory bowel disease in the German population. PLoS One. 2013;8(1):e54338. Epub 2013/02/01.

Jung C, Colombel JF, Lemann M, Beaugerie L, Allez M, Cosnes J, et al. Genotype/phenotype analyses for 53 Crohn's disease associated genetic polymorphisms. PLoS One. 2012;7(12):e52223. Epub 2013/01/10.

Baskaran K, Pugazhendhi S, Ramakrishna BS. Association of IRGM gene mutations with inflammatory bowel disease in the Indian population. PLoS One. 2014;9(9):e106863. Epub 2014/09/06.

Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, et al. 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(3):242-5. Epub 2011/02/01.