Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKD3O5Z)

• DOT Name: Immunity-related GTPase family M protein (IRGM)
• Synonyms: EC 3.6.5.-; Immunity-related GTPase family M protein 1; Interferon-inducible protein 1; LPS-stimulated RAW 264.7 macrophage protein 47 homolog; LRG-47
• Gene Name: IRGM
• Related Disease:
  Arteriosclerosis
  Arthritis
  Atherosclerosis
  Coeliac disease
  Colitis
  Fatty liver disease
  Gastroenteritis
  Glioma
  Hepatitis C virus infection
  Immunodeficiency
  Inflammatory bowel disease
  Invasive candidiasis
  Irritable bowel syndrome
  Leprosy
  Multiple sclerosis
  Nervous system inflammation
  Non-alcoholic fatty liver disease
  Advanced cancer
  Asthma
  Bacterial infection
  Inflammation
  Language disorder
  Autoimmune disease
  Hepatocellular carcinoma
  Lupus nephritis
  Psoriasis
  Pulmonary tuberculosis
  Sclerosing cholangitis
  Streptococcal pneumonia
  Systemic lupus erythematosus
• UniProt ID: IRGM_HUMAN
• EC Number: 3.6.5.-
• Pfam ID: PF05049
• Sequence:
  MEAMNVEKASADGNLPEVISNIKETLKIVSRTPVNITMAGDSGNGMSTFISALRNTGHEG
  KASPPTELVKATQRCASYFSSHFSNVVLWDLPGTGSATTTLENYLMEMQFNRYDFIMVAS
  AQFSMNHVMLAKTAEDMGKKFYIVWTKLDMDLSTGALPEVQLLQIRENVLENLQKERVCE
  Y
• Function: Immunity-related GTPase that plays important roles in innate immunity and inflammatory response. Acts as a dynamin-like protein that binds to intracellular membranes and promotes remodeling and trafficking of those membranes. Required for clearance of acute protozoan and bacterial infections by interacting with autophagy and lysosome regulatory proteins, thereby promoting the fusion of phagosomes with lysosomes for efficient degradation of cargo including microbes. Regulates selective autophagy, including xenophagy and mitophagy, both directly and indirectly. Directly regulates autophagy by acting as a molecular adapter that promotes the coassembly of the core autophagy machinery to mediate antimicrobial defense: IRGM (1) activates AMPK, which in turn phosphorylates ULK1 and BECN1 to induce autophagy, (2) promotes the coassembly of ULK1 and BECN1, enhancing BECN1-interacting partners and (3) influences the composition of the BECN1 complex, by competing with the negative regulators BCL2 and RUBCN, to trigger autophagy. Also activates autophagy by promoting recruitment of STX17 to autophagosomes. In collaboration with ATG8 proteins, regulate lysosomal biogenesis, a fundamental process for any autophagic pathway, by promoting TFEB dephosphorylation. Also modulates autophagy by assisting with autophagosome formation and preventing lysosomal deacidification. While activating autophagy, acts as a key negative regulator of the inflammatory and interferon responses both by (1) promoting mitophagy and (2) mediating autophagy-dependent degradation of effectors of the inflammatory response. Promotes degradation of damaged and IFNG/IFN-gamma-stressed mitochondria via mitophagy, preventing cytosolic release of ligands that activate inflammation. Acts as a suppressor of inflammation by promoting recruitment of inflammation effectors, such as CGAS, RIGI/RIG-I and NLRP3, to autophagosome membranes, leading to their SQSTM1/p62-dependent autophagic degradation. Also directly inhibits assembly of the NLRP3 inflammasome by preventing the association between NLRP3 and PYCARD. Acts as a negative regulator of antiviral innate immune response by suppressing the RIPK2-dependent pro-inflammatory response: mediates recruitment of RIPosomes, composed of RIPK2 and NOD1 or NOD2, to autophagosome membranes, promoting their SQSTM1/p62-dependent autophagic degradation ; [Isoform IRGMd]: Acts as a positive regulator of mitophagy in response to intracellular mycobacteria infection: specifically binds cardiolipin, leading to its translocation to mitochondria, where it promotes affected mitochondrial fission and mitophagy; (Microbial infection) Following infection by hepatitis C virus (HCV), promotes HCV-triggered membrane remodeling, leading to autophagy and Golgi fragmentation, a step required for HCV replication.
• Tissue Specificity: Widely expressed (at protein level) . Expressed in several tissues including colon, small bowel and peripheral blood leukocytes .
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Toxoplasmosis (hsa05145)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[1]
Arthritis	DIST1YEL	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[1]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[3]
Colitis	DISAF7DD	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[5]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[8]
Immunodeficiency	DIS093I0	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[10]
Invasive candidiasis	DIS5EI0L	Strong	Biomarker	[11]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[12]
Leprosy	DISAA4UI	Strong	Genetic Variation	[13]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[14]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[15]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[16]
Asthma	DISW9QNS	moderate	Genetic Variation	[17]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[18]
Inflammation	DISJUQ5T	moderate	Biomarker	[19]
Language disorder	DISTLKP7	moderate	Genetic Variation	[16]
Autoimmune disease	DISORMTM	Limited	Biomarker	[20]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[21]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[22]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[23]
Pulmonary tuberculosis	DIS6FLUM	Limited	Genetic Variation	[24]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[23]
Streptococcal pneumonia	DIS2EKMJ	Limited	Biomarker	[20]
Systemic lupus erythematosus	DISI1SZ7	Limited	Biomarker	[22]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Immunity-related GTPase family M protein (IRGM).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Immunity-related GTPase family M protein (IRGM).	[26]

3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Immunity-related GTPase family M protein (IRGM).	[27]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Immunity-related GTPase family M protein (IRGM).	[28]
Ginsenoside Re	DM46FVD	Investigative	Ginsenoside Re decreases the expression of Immunity-related GTPase family M protein (IRGM).	[29]

References

• [1] Irgm1 promotes M1 but not M2 macrophage polarization in atherosclerosis pathogenesis and development.Atherosclerosis. 2016 Aug;251:282-290. doi: 10.1016/j.atherosclerosis.2016.07.011. Epub 2016 Jul 10.
• [2] Genetic polymorphisms of ATG16L1 and IRGM genes in Malaysian patients with Crohn's disease.J Dig Dis. 2020 Jan;21(1):29-37. doi: 10.1111/1751-2980.12829. Epub 2019 Dec 2.
• [3] Lack of association of NKX2-3, IRGM, and ATG16L1 inflammatory bowel disease susceptibility variants with celiac disease.Hum Immunol. 2009 Nov;70(11):946-9. doi: 10.1016/j.humimm.2009.08.004. Epub 2009 Aug 13.
• [4] IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy.Autophagy. 2019 Sep;15(9):1645-1647. doi: 10.1080/15548627.2019.1628544. Epub 2019 Jun 20.
• [5] The immunity-related GTPase M rs13361189 variant does not increase the risk for prevalent or incident steatosis; results from the Framingham Heart Study.Liver Int. 2019 Jun;39(6):1022-1026. doi: 10.1111/liv.14039. Epub 2019 Feb 17.
• [6] Abnormalities in the handling of intracellular bacteria in Crohn's disease.J Clin Gastroenterol. 2010 Sep;44 Suppl 1:S26-9. doi: 10.1097/MCG.0b013e3181dd4fa5.
• [7] High expression of immunity-related GTPase family M protein in glioma promotes cell proliferation and autophagy protein expression.Pathol Res Pract. 2019 Jan;215(1):90-96. doi: 10.1016/j.prp.2018.10.004. Epub 2018 Oct 24.
• [8] Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M.Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):E3462-E3471. doi: 10.1073/pnas.1616683114. Epub 2017 Apr 7.
• [9] Irgm1 (LRG-47), a regulator of cell-autonomous immunity, does not localize to mycobacterial or listerial phagosomes in IFN--induced mouse cells.J Immunol. 2013 Aug 15;191(4):1765-74. doi: 10.4049/jimmunol.1300641. Epub 2013 Jul 10.
• [10] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [11] Role of autophagy genetic variants for the risk of Candida infections.Med Mycol. 2014 May;52(4):333-41. doi: 10.1093/mmy/myt035. Epub 2014 Apr 8.
• [12] Autophagy-related IRGM genes confer susceptibility to ankylosing spondylitis in a Chinese female population: a case-control study.Genes Immun. 2017 Jan;18(1):42-47. doi: 10.1038/gene.2016.48. Epub 2016 Dec 29.
• [13] Autophagy gene polymorphism is associated with susceptibility to leprosy by affecting inflammatory cytokines.Inflammation. 2014 Apr;37(2):593-8. doi: 10.1007/s10753-013-9773-1.
• [14] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [15] Irgm1 is required for the inflammatory function of M1 macrophage in early experimental autoimmune encephalomyelitis.J Leukoc Biol. 2017 Feb;101(2):507-517. doi: 10.1189/jlb.3A0116-028RR. Epub 2016 Jul 21.
• [16] Functional IRGM polymorphism is associated with language impairment in glioma and upregulates cytokine expressions.Tumour Biol. 2014 Aug;35(8):8343-8. doi: 10.1007/s13277-014-2091-x. Epub 2014 May 24.
• [17] Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.Eur J Hum Genet. 2011 Apr;19(4):458-64. doi: 10.1038/ejhg.2010.191. Epub 2010 Dec 8.
• [18] Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.J Biol Chem. 2017 Mar 17;292(11):4651-4662. doi: 10.1074/jbc.M116.770735. Epub 2017 Feb 1.
• [19] Role of autophagy and autophagy genes in inflammatory bowel disease.Curr Top Microbiol Immunol. 2009;335:141-67. doi: 10.1007/978-3-642-00302-8_7.
• [20] Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces.JCI Insight. 2017 Aug 17;2(16):e91914. doi: 10.1172/jci.insight.91914. eCollection 2017 Aug 17.
• [21] AGBL2 promotes cancer cell growth through IRGM-regulated autophagy and enhanced Aurora A activity in hepatocellular carcinoma.Cancer Lett. 2018 Feb 1;414:71-80. doi: 10.1016/j.canlet.2017.11.003. Epub 2017 Nov 8.
• [22] Podocytes and autophagy: a potential therapeutic target in lupus nephritis.Autophagy. 2019 May;15(5):908-912. doi: 10.1080/15548627.2019.1580512. Epub 2019 Feb 17.
• [23] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [24] IRGM gene polymorphisms and haplotypes associate with susceptibility of pulmonary tuberculosis in Chinese Hubei Han population.Tuberculosis (Edinb). 2016 Jan;96:58-64. doi: 10.1016/j.tube.2015.10.014. Epub 2015 Dec 8.
• [25] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [28] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.
• [29] Ginsenoside Re enhances survival of human CD4+ T cells through regulation of autophagy. Int Immunopharmacol. 2010 May;10(5):626-31. doi: 10.1016/j.intimp.2010.03.002. Epub 2010 Mar 15.