IRGM_HUMAN
ID IRGM_HUMAN Reviewed; 181 AA.
AC A1A4Y4; B3VEX0;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 18-MAR-2008, sequence version 2.
DT 03-AUG-2022, entry version 122.
DE RecName: Full=Immunity-related GTPase family M protein;
DE EC=3.6.5.-;
DE AltName: Full=Immunity-related GTPase family M protein 1;
DE AltName: Full=Interferon-inducible protein 1;
DE AltName: Full=LPS-stimulated RAW 264.7 macrophage protein 47 homolog;
DE Short=LRG-47;
GN Name=IRGM; Synonyms=IFI1, IRGM1, LRG47;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=19266026; DOI=10.1371/journal.pgen.1000403;
RA Bekpen C., Marques-Bonet T., Alkan C., Antonacci F., Leogrande M.B.,
RA Ventura M., Kidd J.M., Siswara P., Howard J.C., Eichler E.E.;
RT "Death and resurrection of the human IRGM gene.";
RL PLoS Genet. 5:E1000403-E1000403(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION, AND INDUCTION.
RX PubMed=16277747; DOI=10.1186/gb-2005-6-11-r92;
RA Bekpen C., Hunn J.P., Rohde C., Parvanova I., Guethlein L., Dunn D.M.,
RA Glowalla E., Leptin M., Howard J.C.;
RT "The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the
RT cell autonomous resistance mechanism in the human lineage.";
RL Genome Biol. 6:R92.1-R92.18(2005).
RN [5]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16888103; DOI=10.1126/science.1129577;
RA Singh S.B., Davis A.S., Taylor G.A., Deretic V.;
RT "Human IRGM induces autophagy to eliminate intracellular mycobacteria.";
RL Science 313:1438-1441(2006).
RN [6]
RP INVOLVEMENT IN IBD19, VARIANTS ASP-17 AND LYS-94, AND TISSUE SPECIFICITY.
RX PubMed=17554261; DOI=10.1038/ng2061;
RA Parkes M., Barrett J.C., Prescott N.J., Tremelling M., Anderson C.A.,
RA Fisher S.A., Roberts R.G., Nimmo E.R., Cummings F.R., Soars D.,
RA Drummond H., Lees C.W., Khawaja S.A., Bagnall R., Burke D.A.,
RA Todhunter C.E., Ahmad T., Onnie C.M., McArdle W., Strachan D., Bethel G.,
RA Bryan C., Lewis C.M., Deloukas P., Forbes A., Sanderson J., Jewell D.P.,
RA Satsangi J., Mansfield J.C., Cardon L., Mathew C.G.;
RT "Sequence variants in the autophagy gene IRGM and multiple other
RT replicating loci contribute to Crohn's disease susceptibility.";
RL Nat. Genet. 39:830-832(2007).
RN [7]
RP INVOLVEMENT IN IBD19.
RX PubMed=19174780; DOI=10.1038/ajg.2008.112;
RA Weersma R.K., Stokkers P.C., Cleynen I., Wolfkamp S.C., Henckaerts L.,
RA Schreiber S., Dijkstra G., Franke A., Nolte I.M., Rutgeerts P.,
RA Wijmenga C., Vermeire S.;
RT "Confirmation of multiple Crohn's disease susceptibility loci in a large
RT Dutch-Belgian cohort.";
RL Am. J. Gastroenterol. 104:630-638(2009).
RN [8]
RP INVOLVEMENT IN IBD19.
RX PubMed=21278745; DOI=10.1038/ng.762;
RA Brest P., Lapaquette P., Souidi M., Lebrigand K., Cesaro A.,
RA Vouret-Craviari V., Mari B., Barbry P., Mosnier J.F., Hebuterne X.,
RA Harel-Bellan A., Mograbi B., Darfeuille-Michaud A., Hofman P.;
RT "A synonymous variant in IRGM alters a binding site for miR-196 and causes
RT deregulation of IRGM-dependent xenophagy in Crohn's disease.";
RL Nat. Genet. 43:242-245(2011).
CC -!- FUNCTION: Putative GTPase which is required for clearance of acute
CC protozoan and bacterial infections. Functions in innate immune response
CC probably through regulation of autophagy. May regulate pro-inflammatory
CC cytokine production and prevent endotoxemia upon infection. May also
CC play a role in macrophages adhesion and motility (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:16888103}.
CC -!- INTERACTION:
CC A1A4Y4; Q96CV9: OPTN; NbExp=3; IntAct=EBI-20844678, EBI-748974;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane {ECO:0000250}. Cell
CC membrane {ECO:0000250}. Cytoplasmic vesicle, phagosome membrane
CC {ECO:0000250}. Cytoplasmic vesicle, autophagosome membrane
CC {ECO:0000250}. Cell projection, phagocytic cup {ECO:0000250}.
CC Note=Behaves like an integral membrane protein. Recruited to the plasma
CC membrane around forming phagocytic cups, it remains associated with
CC maturing autophagosomes. Preferentially associated with cis- and
CC medial-Golgi. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Widely expressed (at protein level). Expressed in
CC several tissues including colon, small bowel and peripheral blood
CC leukocytes. {ECO:0000269|PubMed:16888103, ECO:0000269|PubMed:17554261}.
CC -!- INDUCTION: Not up-regulated by IFNG/IFN-gamma.
CC {ECO:0000269|PubMed:16277747}.
CC -!- DOMAIN: The G5 motif of the IRG-type G domain is missing because the
CC IRGM protein is truncated in anthropoids.
CC -!- DISEASE: Inflammatory bowel disease 19 (IBD19) [MIM:612278]: A chronic,
CC relapsing inflammation of the gastrointestinal tract with a complex
CC etiology. It is subdivided into Crohn disease and ulcerative colitis
CC phenotypes. Crohn disease may affect any part of the gastrointestinal
CC tract from the mouth to the anus, but most frequently it involves the
CC terminal ileum and colon. Bowel inflammation is transmural and
CC discontinuous; it may contain granulomas or be associated with
CC intestinal or perianal fistulas. In contrast, in ulcerative colitis,
CC the inflammation is continuous and limited to rectal and colonic
CC mucosal layers; fistulas and granulomas are not observed. Both diseases
CC include extraintestinal inflammation of the skin, eyes, or joints.
CC {ECO:0000269|PubMed:17554261, ECO:0000269|PubMed:19174780,
CC ECO:0000269|PubMed:21278745}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Depletion of IRGM by siRNA favors mycobacteria survival
CC in macrophages.
CC -!- MISCELLANEOUS: There is a huge difference in terms of sequence and
CC regulation of expression compared to the mouse ortholog and hence, the
CC function might be slightly different. {ECO:0000305|PubMed:16277747}.
CC -!- SIMILARITY: Belongs to the TRAFAC class dynamin-like GTPase
CC superfamily. IRG family. {ECO:0000255|PROSITE-ProRule:PRU01053,
CC ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAI28169.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=EAW61704.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; EU742619; ACF21844.1; -; mRNA.
DR EMBL; FJ824056; ACO88909.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61704.1; ALT_INIT; Genomic_DNA.
DR EMBL; BC128167; AAI28168.1; -; mRNA.
DR EMBL; BC128168; AAI28169.1; ALT_INIT; mRNA.
DR CCDS; CCDS47313.1; -.
DR RefSeq; NP_001139277.1; NM_001145805.1.
DR AlphaFoldDB; A1A4Y4; -.
DR SMR; A1A4Y4; -.
DR BioGRID; 131358; 21.
DR IntAct; A1A4Y4; 2.
DR STRING; 9606.ENSP00000428220; -.
DR iPTMnet; A1A4Y4; -.
DR PhosphoSitePlus; A1A4Y4; -.
DR BioMuta; IRGM; -.
DR PaxDb; A1A4Y4; -.
DR PeptideAtlas; A1A4Y4; -.
DR PRIDE; A1A4Y4; -.
DR Antibodypedia; 28102; 279 antibodies from 27 providers.
DR DNASU; 345611; -.
DR Ensembl; ENST00000522154.2; ENSP00000428220.1; ENSG00000237693.5.
DR GeneID; 345611; -.
DR KEGG; hsa:345611; -.
DR MANE-Select; ENST00000522154.2; ENSP00000428220.1; NM_001145805.2; NP_001139277.1.
DR UCSC; uc010jhk.3; human.
DR CTD; 345611; -.
DR DisGeNET; 345611; -.
DR GeneCards; IRGM; -.
DR HGNC; HGNC:29597; IRGM.
DR HPA; ENSG00000237693; Tissue enhanced (brain).
DR MalaCards; IRGM; -.
DR MIM; 608212; gene.
DR MIM; 612278; phenotype.
DR neXtProt; NX_A1A4Y4; -.
DR OpenTargets; ENSG00000237693; -.
DR Orphanet; 206; NON RARE IN EUROPE: Crohn disease.
DR PharmGKB; PA142671652; -.
DR VEuPathDB; HostDB:ENSG00000237693; -.
DR eggNOG; ENOG502QS9R; Eukaryota.
DR GeneTree; ENSGT00950000183007; -.
DR HOGENOM; CLU_015342_0_0_1; -.
DR InParanoid; A1A4Y4; -.
DR OMA; KEQVCEH; -.
DR OrthoDB; 688334at2759; -.
DR PhylomeDB; A1A4Y4; -.
DR PathwayCommons; A1A4Y4; -.
DR SignaLink; A1A4Y4; -.
DR BioGRID-ORCS; 345611; 2 hits in 1069 CRISPR screens.
DR ChiTaRS; IRGM; human.
DR GeneWiki; IRGM; -.
DR GenomeRNAi; 345611; -.
DR Pharos; A1A4Y4; Tbio.
DR PRO; PR:A1A4Y4; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; A1A4Y4; protein.
DR Bgee; ENSG00000237693; Expressed in granulocyte and 98 other tissues.
DR ExpressionAtlas; A1A4Y4; baseline and differential.
DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0001891; C:phagocytic cup; IEA:UniProtKB-SubCell.
DR GO; GO:0030670; C:phagocytic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0051434; F:BH3 domain binding; IMP:UniProtKB.
DR GO; GO:0050700; F:CARD domain binding; IMP:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IBA:GO_Central.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IMP:UniProtKB.
DR GO; GO:0000045; P:autophagosome assembly; IMP:UniProtKB.
DR GO; GO:0061762; P:CAMKK-AMPK signaling cascade; IMP:UniProtKB.
DR GO; GO:0035458; P:cellular response to interferon-beta; IBA:GO_Central.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IMP:UniProtKB.
DR GO; GO:0098586; P:cellular response to virus; IMP:UniProtKB.
DR GO; GO:0006952; P:defense response; IBA:GO_Central.
DR GO; GO:0042742; P:defense response to bacterium; IMP:UniProtKB.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IMP:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IMP:UniProtKB.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IMP:UniProtKB.
DR GO; GO:1901098; P:positive regulation of autophagosome maturation; IMP:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB.
DR GO; GO:0060335; P:positive regulation of interferon-gamma-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IMP:UniProtKB.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IMP:UniProtKB.
DR GO; GO:0031648; P:protein destabilization; IMP:UniProtKB.
DR GO; GO:0061739; P:protein lipidation involved in autophagosome assembly; IMP:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB.
DR GO; GO:0061635; P:regulation of protein complex stability; IMP:UniProtKB.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IMP:UniProtKB.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR030385; G_IRG_dom.
DR InterPro; IPR007743; Immunity-related_GTPase-like.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF05049; IIGP; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS51716; G_IRG; 1.
PE 1: Evidence at protein level;
KW Autophagy; Cell membrane; Cell projection; Cytoplasmic vesicle;
KW Golgi apparatus; GTP-binding; Hydrolase; Immunity; Inflammatory response;
KW Innate immunity; Membrane; Nucleotide-binding; Reference proteome.
FT CHAIN 1..181
FT /note="Immunity-related GTPase family M protein"
FT /id="PRO_0000325749"
FT DOMAIN 32..181
FT /note="IRG-type G"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01053"
FT BINDING 41..48
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250"
FT BINDING 66..70
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250"
FT BINDING 147..149
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250"
FT VARIANT 17
FT /note="E -> D (in dbSNP:rs180802994)"
FT /evidence="ECO:0000269|PubMed:17554261"
FT /id="VAR_039899"
FT VARIANT 94
FT /note="T -> K (in dbSNP:rs72553867)"
FT /evidence="ECO:0000269|PubMed:17554261"
FT /id="VAR_039900"
SQ SEQUENCE 181 AA; 20142 MW; D8FB5A6D6968E2EE CRC64;
MEAMNVEKAS ADGNLPEVIS NIKETLKIVS RTPVNITMAG DSGNGMSTFI SALRNTGHEG
KASPPTELVK ATQRCASYFS SHFSNVVLWD LPGTGSATTT LENYLMEMQF NRYDFIMVAS
AQFSMNHVML AKTAEDMGKK FYIVWTKLDM DLSTGALPEV QLLQIRENVL ENLQKERVCE
Y
