ICOS_HUMAN
ID ICOS_HUMAN Reviewed; 199 AA.
AC Q9Y6W8; Q8N6W8;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Inducible T-cell costimulator;
DE AltName: Full=Activation-inducible lymphocyte immunomediatory molecule;
DE AltName: CD_antigen=CD278;
DE Flags: Precursor;
GN Name=ICOS; Synonyms=AILIM;
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 (ISOFORM 1), PROTEIN SEQUENCE OF 192-198, FUNCTION,
RP SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=9930702; DOI=10.1038/16717;
RA Hutloff A., Dittrich A.M., Beier K.C., Eljaschewitsch B., Kraft R.,
RA Anagnostopoulos I., Kroczek R.A.;
RT "ICOS is an inducible T-cell co-stimulator structurally and functionally
RT related to CD28.";
RL Nature 397:263-266(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Blood;
RX PubMed=11006126; DOI=10.1006/bbrc.2000.3466;
RA Tezuka K., Tsuji T., Hirano D., Tamatani T., Sakamaki K., Kobayashi Y.,
RA Kamada M.;
RT "Identification and characterization of rat AILIM/ICOS, a novel T-cell
RT costimulatory molecule, related to the CD28/CTLA4 family.";
RL Biochem. Biophys. Res. Commun. 276:335-345(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE (ISOFORM 1).
RC TISSUE=Thymus;
RX PubMed=10779774; DOI=10.4049/jimmunol.164.9.4689;
RA Aicher A., Hayden-Ledbetter M., Brady W.A., Pezzutto A., Richter G.,
RA Magaletti D., Buckwalter S., Ledbetter J.A., Clark E.A.;
RT "Characterization of human inducible costimulator ligand expression and
RT function.";
RL J. Immunol. 164:4689-4696(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=11735222; DOI=10.1006/geno.2001.6655;
RA Ling V., Wu P.W., Finnerty H.F., Agostino M.J., Graham J.R., Chen S.,
RA Jussiff J.M., Fisk G.J., Miller C.P., Collins M.;
RT "Assembly and annotation of human chromosome 2q33 sequence containing the
RT CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative,
RT and microarray approaches.";
RL Genomics 78:155-168(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE (ISOFORM 1).
RX PubMed=12753665; DOI=10.1034/j.1399-0039.2003.00019.x;
RA Haaning Andersen A.D., Lange M., Lillevang S.T.;
RT "Allelic variation of the inducible costimulator (ICOS) gene: detection of
RT polymorphisms, analysis of the promoter region, and extended haplotype
RT estimation.";
RL Tissue Antigens 61:276-285(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE (ISOFORM 1).
RA Todd J.A.;
RL Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Blood;
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 [8]
RP FUNCTION, GLYCOSYLATION, SUBUNIT, INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=11169414;
RX DOI=10.1002/1521-4141(200012)30:12<3707::aid-immu3707>3.0.co;2-q;
RA Beier K.C., Hutloff A., Dittrich A.M., Heuck C., Rauch A., Buechner K.,
RA Ludewig B., Ochs H.D., Mages H.W., Kroczek R.A.;
RT "Induction, binding specificity and function of human ICOS.";
RL Eur. J. Immunol. 30:3707-3717(2000).
RN [9]
RP INVOLVEMENT IN CVID1.
RX PubMed=12577056; DOI=10.1038/ni902;
RA Grimbacher B., Hutloff A., Schlesier M., Glocker E., Warnatz K.,
RA Draeger R., Eibel H., Fischer B., Schaeffer A.A., Mages H.W., Kroczek R.A.,
RA Peter H.H.;
RT "Homozygous loss of ICOS is associated with adult-onset common variable
RT immunodeficiency.";
RL Nat. Immunol. 4:261-268(2003).
CC -!- FUNCTION: Enhances all basic T-cell responses to a foreign antigen,
CC namely proliferation, secretion of lymphokines, up-regulation of
CC molecules that mediate cell-cell interaction, and effective help for
CC antibody secretion by B-cells. Essential both for efficient interaction
CC between T and B-cells and for normal antibody responses to T-cell
CC dependent antigens. Does not up-regulate the production of interleukin-
CC 2, but superinduces the synthesis of interleukin-10. Prevents the
CC apoptosis of pre-activated T-cells. Plays a critical role in CD40-
CC mediated class switching of immunoglobin isotypes (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:11169414, ECO:0000269|PubMed:9930702}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000269|PubMed:11169414,
CC ECO:0000269|PubMed:9930702}.
CC -!- INTERACTION:
CC Q9Y6W8; O75144: ICOSLG; NbExp=8; IntAct=EBI-3922712, EBI-12923856;
CC Q9Y6W8; P27986: PIK3R1; NbExp=5; IntAct=EBI-3922712, EBI-79464;
CC Q9Y6W8; Q9UHD2: TBK1; NbExp=5; IntAct=EBI-3922712, EBI-356402;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane {ECO:0000305}; Single-
CC pass type I membrane protein {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Y6W8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y6W8-2; Sequence=VSP_010788;
CC -!- TISSUE SPECIFICITY: Activated T-cells. Highly expressed on tonsillar T-
CC cells, which are closely associated with B-cells in the apical light
CC zone of germinal centers, the site of terminal B-cell maturation.
CC Expressed at lower levels in thymus, lung, lymph node and peripheral
CC blood leukocytes. Expressed in the medulla of fetal and newborn thymus.
CC {ECO:0000269|PubMed:11006126, ECO:0000269|PubMed:11169414,
CC ECO:0000269|PubMed:9930702}.
CC -!- INDUCTION: By phorbol myristate acetate (PMA) and ionomycin. Up-
CC regulated early on T-cells and continues to be expressed into the later
CC phases of T-cell activation. {ECO:0000269|PubMed:11169414}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:11169414}.
CC -!- DISEASE: Immunodeficiency, common variable, 1 (CVID1) [MIM:607594]: A
CC primary immunodeficiency characterized by antibody deficiency,
CC hypogammaglobulinemia, recurrent bacterial infections and an inability
CC to mount an antibody response to antigen. The defect results from a
CC failure of B-cell differentiation and impaired secretion of
CC immunoglobulins; the numbers of circulating B-cells is usually in the
CC normal range, but can be low. {ECO:0000269|PubMed:12577056}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- WEB RESOURCE: Name=ICOSbase; Note=ICOS mutation db;
CC URL="http://structure.bmc.lu.se/idbase/ICOSbase/";
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DR EMBL; AJ277832; CAC06612.1; -; mRNA.
DR EMBL; AB023135; BAA82129.1; -; mRNA.
DR EMBL; AF218312; AAF71301.1; -; mRNA.
DR EMBL; AF411058; AAL40933.1; -; Genomic_DNA.
DR EMBL; AF411059; AAL40934.1; -; Genomic_DNA.
DR EMBL; AF488347; AAM00909.1; -; Genomic_DNA.
DR EMBL; AF488346; AAM00909.1; JOINED; Genomic_DNA.
DR EMBL; AJ535718; CAD59742.1; -; Genomic_DNA.
DR EMBL; BC028006; AAH28006.1; -; mRNA.
DR EMBL; BC028210; AAH28210.1; -; mRNA.
DR CCDS; CCDS2363.1; -. [Q9Y6W8-1]
DR PIR; S78540; S78540.
DR RefSeq; NP_036224.1; NM_012092.3. [Q9Y6W8-1]
DR PDB; 6X4G; X-ray; 3.50 A; A=19-129.
DR PDB; 7JOO; X-ray; 2.40 A; C=19-138.
DR PDBsum; 6X4G; -.
DR PDBsum; 7JOO; -.
DR AlphaFoldDB; Q9Y6W8; -.
DR SMR; Q9Y6W8; -.
DR BioGRID; 118933; 28.
DR IntAct; Q9Y6W8; 13.
DR STRING; 9606.ENSP00000319476; -.
DR ChEMBL; CHEMBL3712953; -.
DR GuidetoPHARMACOLOGY; 2939; -.
DR GlyGen; Q9Y6W8; 3 sites.
DR iPTMnet; Q9Y6W8; -.
DR PhosphoSitePlus; Q9Y6W8; -.
DR BioMuta; ICOS; -.
DR DMDM; 50400701; -.
DR MassIVE; Q9Y6W8; -.
DR PaxDb; Q9Y6W8; -.
DR PeptideAtlas; Q9Y6W8; -.
DR PRIDE; Q9Y6W8; -.
DR ProteomicsDB; 86805; -. [Q9Y6W8-1]
DR ProteomicsDB; 86806; -. [Q9Y6W8-2]
DR ABCD; Q9Y6W8; 2 sequenced antibodies.
DR Antibodypedia; 34168; 1030 antibodies from 42 providers.
DR DNASU; 29851; -.
DR Ensembl; ENST00000316386.11; ENSP00000319476.6; ENSG00000163600.13. [Q9Y6W8-1]
DR Ensembl; ENST00000435193.1; ENSP00000415951.1; ENSG00000163600.13. [Q9Y6W8-2]
DR GeneID; 29851; -.
DR KEGG; hsa:29851; -.
DR MANE-Select; ENST00000316386.11; ENSP00000319476.6; NM_012092.4; NP_036224.1.
DR UCSC; uc002vam.4; human. [Q9Y6W8-1]
DR CTD; 29851; -.
DR DisGeNET; 29851; -.
DR GeneCards; ICOS; -.
DR HGNC; HGNC:5351; ICOS.
DR HPA; ENSG00000163600; Group enriched (bone marrow, lymphoid tissue).
DR MalaCards; ICOS; -.
DR MIM; 604558; gene.
DR MIM; 607594; phenotype.
DR neXtProt; NX_Q9Y6W8; -.
DR OpenTargets; ENSG00000163600; -.
DR Orphanet; 1572; Common variable immunodeficiency.
DR PharmGKB; PA29599; -.
DR VEuPathDB; HostDB:ENSG00000163600; -.
DR eggNOG; ENOG502S59F; Eukaryota.
DR GeneTree; ENSGT00390000000801; -.
DR HOGENOM; CLU_1315009_0_0_1; -.
DR InParanoid; Q9Y6W8; -.
DR OMA; QDKEDCF; -.
DR OrthoDB; 702827at2759; -.
DR PhylomeDB; Q9Y6W8; -.
DR TreeFam; TF335679; -.
DR PathwayCommons; Q9Y6W8; -.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. [Q9Y6W8-1]
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. [Q9Y6W8-1]
DR Reactome; R-HSA-388841; Costimulation by the CD28 family. [Q9Y6W8-1]
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. [Q9Y6W8-1]
DR SignaLink; Q9Y6W8; -.
DR BioGRID-ORCS; 29851; 17 hits in 1060 CRISPR screens.
DR ChiTaRS; ICOS; human.
DR GeneWiki; CD278; -.
DR GenomeRNAi; 29851; -.
DR Pharos; Q9Y6W8; Tbio.
DR PRO; PR:Q9Y6W8; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9Y6W8; protein.
DR Bgee; ENSG00000163600; Expressed in lymph node and 75 other tissues.
DR ExpressionAtlas; Q9Y6W8; baseline and differential.
DR Genevisible; Q9Y6W8; HS.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0098609; P:cell-cell adhesion; IBA:GO_Central.
DR GO; GO:0006955; P:immune response; NAS:UniProtKB.
DR GO; GO:0031295; P:T cell costimulation; IBA:GO_Central.
DR GO; GO:0002517; P:T cell tolerance induction; IBA:GO_Central.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR039943; ICOS.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013106; Ig_V-set.
DR PANTHER; PTHR20904; PTHR20904; 1.
DR Pfam; PF15910; V-set_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Immunoglobulin domain; Membrane; Reference proteome; Secreted; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT CHAIN 21..199
FT /note="Inducible T-cell costimulator"
FT /id="PRO_0000014806"
FT TOPO_DOM 21..140
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 141..161
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 162..199
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 30..132
FT /note="Ig-like V-type"
FT CARBOHYD 23
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 89
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 110
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 42..109
FT /evidence="ECO:0000250"
FT DISULFID 63..83
FT /evidence="ECO:0000250"
FT VAR_SEQ 168..199
FT /note="KYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL -> M (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_010788"
FT STRAND 31..33
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 35..43
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 50..57
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 60..69
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 75..78
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 84..87
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 89..96
FT /evidence="ECO:0007829|PDB:7JOO"
FT HELIX 101..103
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 106..118
FT /evidence="ECO:0007829|PDB:7JOO"
FT STRAND 120..127
FT /evidence="ECO:0007829|PDB:7JOO"
SQ SEQUENCE 199 AA; 22625 MW; 214EC741C9BDC9FC CRC64;
MKSGLWYFFL FCLRIKVLTG EINGSANYEM FIFHNGGVQI LCKYPDIVQQ FKMQLLKGGQ
ILCDLTKTKG SGNTVSIKSL KFCHSQLSNN SVSFFLYNLD HSHANYYFCN LSIFDPPPFK
VTLTGGYLHI YESQLCCQLK FWLPIGCAAF VVVCILGCIL ICWLTKKKYS SSVHDPNGEY
MFMRAVNTAK KSRLTDVTL
