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   27-MAR-2024, entry version 181.
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   GlyCosmos; Q9Y6W8; 3 sites, No reported glycans.
DR   GlyGen; Q9Y6W8; 3 sites.
DR   iPTMnet; Q9Y6W8; -.
DR   PhosphoSitePlus; Q9Y6W8; -.
DR   BioMuta; ICOS; -.
DR   DMDM; 50400701; -.
DR   MassIVE; Q9Y6W8; -.
DR   PaxDb; 9606-ENSP00000319476; -.
DR   PeptideAtlas; Q9Y6W8; -.
DR   ProteomicsDB; 86805; -. [Q9Y6W8-1]
DR   ProteomicsDB; 86806; -. [Q9Y6W8-2]
DR   ABCD; Q9Y6W8; 2 sequenced antibodies.
DR   Antibodypedia; 34168; 1181 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   AGR; HGNC:5351; -.
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; 4570780at2759; -.
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   SIGNOR; Q9Y6W8; -.
DR   BioGRID-ORCS; 29851; 18 hits in 1137 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 76 other cell types or tissues.
DR   ExpressionAtlas; Q9Y6W8; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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; Immunoglobulins; 1.
DR   InterPro; IPR039943; ICOS.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR013106; Ig_V-set.
DR   PANTHER; PTHR20904:SF0; INDUCIBLE T-CELL COSTIMULATOR; 1.
DR   PANTHER; PTHR20904; INDUCIBLE T-CELL COSTIMULATOR ICOS; 1.
DR   Pfam; PF15910; V-set_2; 1.
DR   Genevisible; Q9Y6W8; HS.
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
//