ID IL18_MOUSE Reviewed; 192 AA. AC P70380; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 15-JUL-1998, sequence version 2. DT 27-MAR-2024, entry version 175. DE RecName: Full=Interleukin-18; DE Short=IL-18; DE AltName: Full=Interferon gamma-inducing factor; DE Short=IFN-gamma-inducing factor; DE AltName: Full=Interleukin-1 gamma; DE Short=IL-1 gamma; DE Flags: Precursor; GN Name=Il18 {ECO:0000312|MGI:MGI:107936}; Synonyms=Igif; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Liver; RX PubMed=7477296; DOI=10.1038/378088a0; RA Okamura H., Tsutui H., Komatsu T., Yutsudo M., Hakura A., Tanimoto T., RA Torigoe K., Okura T., Nukada Y., Hattori K., Akita K., Namba M., Tanabe F., RA Konishi K., Fukuda S., Kurimoto M.; RT "Cloning of a new cytokine that induces IFN-gamma production by T cells."; RL Nature 378:88-91(1995). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=FVB/N; TISSUE=Colon; 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 [3] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-191. RC STRAIN=NOD; TISSUE=Pancreas; RX PubMed=9022080; DOI=10.1172/jci119181; RA Rothe H., Jenkins N.A., Copeland N.G., Kolb H.; RT "Active stage of autoimmune diabetes is associated with the expression of a RT novel cytokine, IGIF, which is located near Idd2."; RL J. Clin. Invest. 99:469-474(1997). RN [4] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, and Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [5] RP FUNCTION. RX PubMed=26638072; DOI=10.1016/j.cell.2015.10.048; RA Levy M., Thaiss C.A., Zeevi D., Dohnalova L., Zilberman-Schapira G., RA Mahdi J.A., David E., Savidor A., Korem T., Herzig Y., Pevsner-Fischer M., RA Shapiro H., Christ A., Harmelin A., Halpern Z., Latz E., Flavell R.A., RA Amit I., Segal E., Elinav E.; RT "Microbiota-modulated metabolites shape the intestinal microenvironment by RT regulating NLRP6 inflammasome signaling."; RL Cell 163:1428-1443(2015). RN [6] RP FUNCTION. RX PubMed=26638073; DOI=10.1016/j.cell.2015.10.072; RA Nowarski R., Jackson R., Gagliani N., de Zoete M.R., Palm N.W., Bailis W., RA Low J.S., Harman C.C., Graham M., Elinav E., Flavell R.A.; RT "Epithelial IL-18 equilibrium controls barrier function in colitis."; RL Cell 163:1444-1456(2015). RN [7] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=30392956; DOI=10.1016/j.cell.2018.09.047; RA Hara H., Seregin S.S., Yang D., Fukase K., Chamaillard M., Alnemri E.S., RA Inohara N., Chen G.Y., Nunez G.; RT "The NLRP6 inflammasome recognizes lipoteichoic acid and regulates Gram- RT positive pathogen infection."; RL Cell 175:1651-1664(2018). RN [8] RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF 28-GLU--ASP-31 AND 36-ASN--HIS-41. RX PubMed=37993712; DOI=10.1038/s41586-023-06751-9; RA Devant P., Dong Y., Mintseris J., Ma W., Gygi S.P., Wu H., Kagan J.C.; RT "Structural insights into cytokine cleavage by inflammatory caspase-4."; RL Nature 0:0-0(2023). RN [9] RP PROTEOLYTIC CLEAVAGE. RX PubMed=37993714; DOI=10.1038/s41586-023-06742-w; RA Shi X., Sun Q., Hou Y., Zeng H., Cao Y., Dong M., Ding J., Shao F.; RT "Recognition and maturation of IL-18 by caspase-4 noncanonical RT inflammasome."; RL Nature 0:0-0(2023). CC -!- FUNCTION: Pro-inflammatory cytokine primarily involved in epithelial CC barrier repair, polarized T-helper 1 (Th1) cell and natural killer (NK) CC cell immune responses (PubMed:26638072, PubMed:26638073). Upon binding CC to IL18R1 and IL18RAP, forms a signaling ternary complex which CC activates NF-kappa-B, triggering synthesis of inflammatory mediators CC (By similarity). Synergizes with IL12/interleukin-12 to induce IFNG CC synthesis from T-helper 1 (Th1) cells and natural killer (NK) cells (By CC similarity). Involved in transduction of inflammation downstream of CC pyroptosis: its mature form is specifically released in the CC extracellular milieu by passing through the gasdermin-D (GSDMD) pore CC (PubMed:30392956). {ECO:0000250|UniProtKB:Q14116, CC ECO:0000269|PubMed:26638072, ECO:0000269|PubMed:26638073, CC ECO:0000269|PubMed:30392956}. CC -!- SUBUNIT: Forms a ternary complex with ligand-binding receptor subunit CC IL18R1 and signaling receptor subunit IL18RAP at the plasma membrane. CC Mature IL18 first binds to IL18R1 forming a low affinity binary CC complex, which then interacts with IL18RAP to form a high affinity CC ternary complex that signals inside the cell. Interacts with cargo CC receptor TMED10; the interaction mediates the translocation from the CC cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate CC compartment) and thereby secretion. {ECO:0000250|UniProtKB:Q14116}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q14116}. CC Secreted {ECO:0000269|PubMed:30392956}. Note=The precursor is cytosolic CC (By similarity). In response to inflammasome-activating signals, CC cleaved and secreted (By similarity). Mature form is secreted and CC released in the extracellular milieu by passing through the gasdermin-D CC (GSDMD) pore (PubMed:30392956). In contrast, the precursor form is not CC released, due to the presence of an acidic region that is CC proteolytically removed by CASP1 during maturation (By similarity). The CC secretion is dependent on protein unfolding and facilitated by the CC cargo receptor TMED10 (By similarity). {ECO:0000250|UniProtKB:Q14116, CC ECO:0000269|PubMed:30392956}. CC -!- PTM: The pro-IL-18 precursor is processed by CASP1 to yield its mature, CC active form (PubMed:37993712, PubMed:37993714). The pro-IL-18 precursor CC is however not processed by Casp4/Casp11 in rodents (PubMed:37993712, CC PubMed:37993714). The pro-IL-18 precursor features autoinhibitory CC interactions between the propeptide and the post-cleavage-site region, CC preventing recognition by the IL18R1 receptor (By similarity). CC Processing by CASP1 induces conformational changes to generate critical CC receptor-binding sites (By similarity). The mature form is then CC secreted and released in the extracellular milieu by passing through CC the gasdermin-D (GSDMD) pore (By similarity). In contrast, cleavage by CC CASP3 inactivates IL18 (By similarity). {ECO:0000250|UniProtKB:Q14116, CC ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714}. CC -!- SIMILARITY: Belongs to the IL-1 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D49949; BAA08705.1; -; mRNA. DR EMBL; BC024384; AAH24384.1; -; mRNA. DR EMBL; U66244; AAB49753.1; -; mRNA. DR CCDS; CCDS40622.1; -. DR PIR; S60226; S60226. DR RefSeq; NP_032386.1; NM_008360.1. DR RefSeq; XP_006510089.1; XM_006510026.1. DR RefSeq; XP_006510090.1; XM_006510027.3. DR RefSeq; XP_006510091.1; XM_006510028.3. DR AlphaFoldDB; P70380; -. DR SMR; P70380; -. DR DIP; DIP-950N; -. DR STRING; 10090.ENSMUSP00000151002; -. DR PhosphoSitePlus; P70380; -. DR PaxDb; 10090-ENSMUSP00000054591; -. DR ProteomicsDB; 266967; -. DR Pumba; P70380; -. DR ABCD; P70380; 1 sequenced antibody. DR Antibodypedia; 1287; 1084 antibodies from 47 providers. DR DNASU; 16173; -. DR Ensembl; ENSMUST00000180021.2; ENSMUSP00000137193.2; ENSMUSG00000039217.14. DR Ensembl; ENSMUST00000214117.2; ENSMUSP00000151002.2; ENSMUSG00000039217.14. DR GeneID; 16173; -. DR KEGG; mmu:16173; -. DR UCSC; uc009pju.1; mouse. DR AGR; MGI:107936; -. DR CTD; 3606; -. DR MGI; MGI:107936; Il18. DR VEuPathDB; HostDB:ENSMUSG00000039217; -. DR eggNOG; ENOG502SDJZ; Eukaryota. DR GeneTree; ENSGT00390000001053; -. DR HOGENOM; CLU_113349_0_0_1; -. DR InParanoid; P70380; -. DR OMA; GKNFCLY; -. DR PhylomeDB; P70380; -. DR BioGRID-ORCS; 16173; 0 hits in 79 CRISPR screens. DR ChiTaRS; Il18; mouse. DR PRO; PR:P70380; -. DR Proteomes; UP000000589; Chromosome 9. DR RNAct; P70380; Protein. DR Bgee; ENSMUSG00000039217; Expressed in epithelium of stomach and 223 other cell types or tissues. DR ExpressionAtlas; P70380; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; ISO:MGI. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IDA:MGI. DR GO; GO:0045515; F:interleukin-18 receptor binding; ISS:UniProtKB. DR GO; GO:0048018; F:receptor ligand activity; IDA:MGI. DR GO; GO:0001525; P:angiogenesis; ISS:UniProtKB. DR GO; GO:0008283; P:cell population proliferation; IDA:MGI. DR GO; GO:0071375; P:cellular response to peptide hormone stimulus; ISO:MGI. DR GO; GO:0042632; P:cholesterol homeostasis; IMP:BHF-UCL. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB. DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; ISO:MGI. DR GO; GO:0061436; P:establishment of skin barrier; IMP:UniProtKB. DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; TAS:UniProtKB. DR GO; GO:0006955; P:immune response; TAS:MGI. DR GO; GO:0006954; P:inflammatory response; IGI:MGI. DR GO; GO:0035655; P:interleukin-18-mediated signaling pathway; IDA:UniProtKB. DR GO; GO:0030101; P:natural killer cell activation; IDA:MGI. DR GO; GO:0042267; P:natural killer cell mediated cytotoxicity; IDA:MGI. DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IMP:MGI. DR GO; GO:0033030; P:negative regulation of neutrophil apoptotic process; ISO:MGI. DR GO; GO:0050732; P:negative regulation of peptidyl-tyrosine phosphorylation; ISO:MGI. DR GO; GO:0042119; P:neutrophil activation; IDA:MGI. DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; ISS:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI. DR GO; GO:2000504; P:positive regulation of blood vessel remodeling; ISO:MGI. DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:MGI. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; IMP:YuBioLab. DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; ISO:MGI. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:MGI. DR GO; GO:0032725; P:positive regulation of granulocyte macrophage colony-stimulating factor production; ISO:MGI. DR GO; GO:2000347; P:positive regulation of hepatocyte proliferation; ISO:MGI. DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:UniProtKB. DR GO; GO:0032736; P:positive regulation of interleukin-13 production; TAS:UniProtKB. DR GO; GO:0032740; P:positive regulation of interleukin-17 production; ISO:MGI. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISO:MGI. DR GO; GO:0010744; P:positive regulation of macrophage derived foam cell differentiation; IMP:BHF-UCL. DR GO; GO:2000256; P:positive regulation of male germ cell proliferation; ISO:MGI. DR GO; GO:0032819; P:positive regulation of natural killer cell proliferation; ISO:MGI. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB. DR GO; GO:0051142; P:positive regulation of NK T cell proliferation; ISO:MGI. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:MGI. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISO:MGI. DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; ISO:MGI. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:MGI. DR GO; GO:0032930; P:positive regulation of superoxide anion generation; ISO:MGI. DR GO; GO:2000556; P:positive regulation of T-helper 1 cell cytokine production; ISS:UniProtKB. DR GO; GO:0045630; P:positive regulation of T-helper 2 cell differentiation; IMP:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:MGI. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:MGI. DR GO; GO:0032729; P:positive regulation of type II interferon production; IDA:MGI. DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISO:MGI. DR GO; GO:0043117; P:positive regulation of vascular permeability; ISO:MGI. DR GO; GO:0030155; P:regulation of cell adhesion; ISS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; ISO:MGI. DR GO; GO:0030431; P:sleep; ISS:UniProtKB. DR GO; GO:0042088; P:T-helper 1 type immune response; ISS:UniProtKB. DR GO; GO:0070328; P:triglyceride homeostasis; IMP:BHF-UCL. DR Gene3D; 2.80.10.50; -; 1. DR InterPro; IPR015529; IL-18. DR InterPro; IPR000975; IL-1_fam. DR InterPro; IPR008996; IL1/FGF. DR PANTHER; PTHR10078; INTERLEUKIN-1 FAMILY MEMBER; 1. DR PANTHER; PTHR10078:SF35; INTERLEUKIN-18; 1. DR Pfam; PF00340; IL1; 1. DR PIRSF; PIRSF015162; Interleukin_18; 1. DR PRINTS; PR01933; INTRLEUKIN18. DR SUPFAM; SSF50353; Cytokine; 1. DR Genevisible; P70380; MM. PE 1: Evidence at protein level; KW Cytokine; Cytoplasm; Direct protein sequencing; Inflammatory response; KW Reference proteome; Secreted. FT PROPEP 1..35 FT /evidence="ECO:0000269|PubMed:7477296" FT /id="PRO_0000015345" FT CHAIN 36..192 FT /note="Interleukin-18" FT /id="PRO_0000015346" FT SITE 35..36 FT /note="Cleavage; by CASP1" FT /evidence="ECO:0000250|UniProtKB:Q14116" FT SITE 69..70 FT /note="Cleavage; by CASP3" FT /evidence="ECO:0000250|UniProtKB:Q14116" FT MUTAGEN 28..31 FT /note="ENGD->DDEN: Humanized protein that is efficiently FT cleaved by Casp4/Casp11; when associated with 36-Y--E-41." FT /evidence="ECO:0000269|PubMed:37993712" FT MUTAGEN 36..41 FT /note="NFGRLH->YFGRLE: Humanized protein that is FT efficiently cleaved by Casp4/Casp11; when associated with FT 28-D--N-41." FT /evidence="ECO:0000269|PubMed:37993712" FT CONFLICT 183..185 FT /note="MFT -> IS (in Ref. 3; AAB49753)" FT /evidence="ECO:0000305" SQ SEQUENCE 192 AA; 22135 MW; 8FED938473874D63 CRC64; MAAMSEDSCV NFKEMMFIDN TLYFIPEENG DLESDNFGRL HCTTAVIRNI NDQVLFVDKR QPVFEDMTDI DQSASEPQTR LIIYMYKDSE VRGLAVTLSV KDSKMSTLSC KNKIISFEEM DPPENIDDIQ SDLIFFQKRV PGHNKMEFES SLYEGHFLAC QKEDDAFKLI LKKKDENGDK SVMFTLTNLH QS //