ID   IL6RA_MOUSE             Reviewed;         460 AA.
AC   P22272;
DT   01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1992, sequence version 2.
DT   27-MAR-2024, entry version 209.
DE   RecName: Full=Interleukin-6 receptor subunit alpha {ECO:0000305};
DE            Short=IL-6 receptor subunit alpha;
DE            Short=IL-6R subunit alpha;
DE            Short=IL-6R-alpha;
DE            Short=IL-6RA;
DE   AltName: Full=IL-6R 1;
DE   AltName: CD_antigen=CD126;
DE   Contains:
DE     RecName: Full=Soluble interleukin-6 receptor subunit alpha {ECO:0000305};
DE              Short=sIL6R {ECO:0000303|PubMed:26876177};
DE   Flags: Precursor;
GN   Name=Il6ra {ECO:0000312|MGI:MGI:105304}; Synonyms=Il6r;
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].
RC   STRAIN=BALB/cJ; TISSUE=Spleen;
RX   PubMed=2112585; DOI=10.1084/jem.171.6.2001;
RA   Sugita T., Totsuka T., Saito M., Yamasaki K., Taga T., Hirano T.,
RA   Kishimoto T.;
RT   "Functional murine interleukin 6 receptor with the intracisternal A
RT   particle gene product at its cytoplasmic domain. Its possible role in
RT   plasmacytomagenesis.";
RL   J. Exp. Med. 171:2001-2009(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=C3H/HeJ; TISSUE=Liver;
RA   Fiorillo M.T., Ciliberto G., Dente L.;
RL   Submitted (JUL-1990) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   FUNCTION (ISOFORM 2).
RX   PubMed=11113088; DOI=10.1053/gast.2000.20236;
RA   Peters M., Blinn G., Jostock T., Schirmacher P.,
RA   Meyer zum Bueschenfelde K.H., Galle P.R., Rose-John S.;
RT   "Combined interleukin 6 and soluble interleukin 6 receptor accelerates
RT   murine liver regeneration.";
RL   Gastroenterology 119:1663-1671(2000).
RN   [4]
RP   FUNCTION, AND INTERACTION WITH SORL1.
RX   PubMed=28265003; DOI=10.1128/mcb.00641-16;
RA   Larsen J.V., Petersen C.M.;
RT   "SorLA in Interleukin-6 Signaling and Turnover.";
RL   Mol. Cell. Biol. 37:0-0(2017).
RN   [5]
RP   FUNCTION, AND PROTEOLYTIC CLEAVAGE.
RX   PubMed=26876177; DOI=10.1016/j.celrep.2016.01.053;
RA   Lokau J., Nitz R., Agthe M., Monhasery N., Aparicio-Siegmund S.,
RA   Schumacher N., Wolf J., Moeller-Hackbarth K., Waetzig G.H., Groetzinger J.,
RA   Mueller-Newen G., Rose-John S., Scheller J., Garbers C.;
RT   "Proteolytic Cleavage Governs Interleukin-11 Trans-signaling.";
RL   Cell Rep. 14:1761-1773(2016).
RN   [6]
RP   FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX   PubMed=28402851; DOI=10.1016/j.celrep.2017.03.043;
RA   Timper K., Denson J.L., Steculorum S.M., Heilinger C., Engstroem-Ruud L.,
RA   Wunderlich C.M., Rose-John S., Wunderlich F.T., Bruening J.C.;
RT   "IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced
RT   Central IL-6 trans-Signaling.";
RL   Cell Rep. 19:267-280(2017).
RN   [7]
RP   FUNCTION, AND TISSUE SPECIFICITY.
RX   PubMed=27893700; DOI=10.1038/ni.3632;
RA   Heink S., Yogev N., Garbers C., Herwerth M., Aly L., Gasperi C.,
RA   Husterer V., Croxford A.L., Moeller-Hackbarth K., Bartsch H.S., Sotlar K.,
RA   Krebs S., Regen T., Blum H., Hemmer B., Misgeld T., Wunderlich T.F.,
RA   Hidalgo J., Oukka M., Rose-John S., Schmidt-Supprian M., Waisman A.,
RA   Korn T.;
RT   "Trans-presentation of IL-6 by dendritic cells is required for the priming
RT   of pathogenic TH17 cells.";
RL   Nat. Immunol. 18:74-85(2017).
RN   [8]
RP   REVIEW ON FUNCTION.
RX   PubMed=30995492; DOI=10.1016/j.immuni.2019.03.026;
RA   Kang S., Tanaka T., Narazaki M., Kishimoto T.;
RT   "Targeting Interleukin-6 Signaling in Clinic.";
RL   Immunity 50:1007-1023(2019).
CC   -!- FUNCTION: Part of the receptor for interleukin 6. Binds to IL6 with low
CC       affinity, but does not transduce a signal. Signal activation
CC       necessitate an association with IL6ST. Activation leads to the
CC       regulation of the immune response, acute-phase reactions and
CC       hematopoiesis. The interaction with membrane-bound IL6R and IL6ST
CC       stimulates 'classic signaling', the restricted expression of the IL6R
CC       limits classic IL6 signaling to only a few tissues such as the liver
CC       and some cells of the immune system. Whereas the binding of IL6 and
CC       soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively,
CC       'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on
CC       transmitter cells activate IL6ST receptors on neighboring receiver
CC       cells. {ECO:0000305|PubMed:30995492}.
CC   -!- FUNCTION: [Interleukin-6 receptor subunit alpha]: Signaling via the
CC       membrane-bound IL6R is mostly regenerative and anti-inflammatory
CC       (Probable). Drives naive CD4(+) T cells to the Th17 lineage, through
CC       'cluster signaling' by dendritic cells (PubMed:27893700).
CC       {ECO:0000269|PubMed:27893700, ECO:0000305|PubMed:30995492}.
CC   -!- FUNCTION: [Soluble interleukin-6 receptor subunit alpha]: Soluble form
CC       of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity
CC       (PubMed:11113088). The IL6:sIL6R complex (hyper-IL6) binds to
CC       IL6ST/gp130 on cell surfaces and induces signaling also on cells that
CC       do not express membrane-bound IL6R in a process called IL6 'trans-
CC       signaling'. sIL6R is causative for the pro-inflammatory properties of
CC       IL6 and an important player in the development of chronic inflammatory
CC       diseases (By similarity). In complex with IL6, is required for
CC       induction of VEGF production (By similarity). Plays a protective role
CC       during liver injury, being required for maintenance of tissue
CC       regeneration (PubMed:11113088). 'Trans-signaling' in central nervous
CC       system regulates energy and glucose homeostasis (PubMed:28402851).
CC       {ECO:0000250|UniProtKB:P08887, ECO:0000269|PubMed:11113088,
CC       ECO:0000269|PubMed:28402851}.
CC   -!- ACTIVITY REGULATION: Classic and trans-signaling are both inhibited by
CC       tocilizumab, a humanized monoclonal antibody that blocks interleukin
CC       IL6R signaling. {ECO:0000250|UniProtKB:P08887}.
CC   -!- SUBUNIT: Component of a hexamer of two molecules each of IL6, IL6R and
CC       IL6ST; first binds to IL6 to associate with the signaling subunit IL6ST
CC       (PubMed:28265003). Interacts (via N-terminal ectodomain) with SORL1;
CC       this interaction may affect IL6-binding to IL6R, hence decrease IL6
CC       'classic-signaling' (PubMed:28265003). {ECO:0000269|PubMed:28265003}.
CC   -!- SUBUNIT: [Soluble interleukin-6 receptor subunit alpha]: Also interacts
CC       with SORL1; this interaction leads to soluble IL6R internalization. May
CC       form a trimeric complex with the soluble SORL1 ectodomain and
CC       circulating IL6 receptor; this interaction might stabilize circulating
CC       IL6, hence promote IL6 'trans-signaling'.
CC       {ECO:0000250|UniProtKB:P08887}.
CC   -!- SUBCELLULAR LOCATION: [Interleukin-6 receptor subunit alpha]: Cell
CC       membrane {ECO:0000269|PubMed:27893700}; Single-pass type I membrane
CC       protein {ECO:0000255}.
CC   -!- SUBCELLULAR LOCATION: [Soluble interleukin-6 receptor subunit alpha]:
CC       Secreted {ECO:0000269|PubMed:28402851}.
CC   -!- TISSUE SPECIFICITY: Expressed by dendritic cells.
CC       {ECO:0000269|PubMed:27893700}.
CC   -!- TISSUE SPECIFICITY: [Soluble interleukin-6 receptor subunit alpha]:
CC       Detected in the cerebrospinal fluid. {ECO:0000269|PubMed:28402851}.
CC   -!- INDUCTION: [Soluble interleukin-6 receptor subunit alpha]: Levels in
CC       the cerebrospinal fluid are increased in obese mice.
CC       {ECO:0000269|PubMed:28402851}.
CC   -!- DOMAIN: The two fibronectin type-III-like domains contained in the C-
CC       terminal part form together a cytokine-binding domain.
CC   -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC       folding and thereby efficient intracellular transport and cell-surface
CC       receptor binding.
CC   -!- PTM: A short soluble form is also released from the membrane by
CC       proteolysis (PubMed:26876177). The sIL6R is formed by limited
CC       proteolysis of membrane-bound receptors, a process referred to as
CC       ectodomain shedding (PubMed:26876177). mIL6R is cleaved by the
CC       proteases ADAM10 and ADAM17 (PubMed:26876177).
CC       {ECO:0000269|PubMed:26876177}.
CC   -!- PTM: Glycosylated. Glycosylation is dispensable for transport,
CC       signaling, and cell-surface turnover. Glycosylation at Asn-55 is a
CC       protease-regulatory exosite. Glycosylation is required for ADAM17-
CC       mediated proteolysis. {ECO:0000250|UniProtKB:P08887}.
CC   -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 3
CC       subfamily. {ECO:0000305}.
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DR   EMBL; X51975; CAA36237.1; -; mRNA.
DR   EMBL; X53802; CAA37810.1; -; mRNA.
DR   CCDS; CCDS38496.1; -.
DR   PIR; JL0144; JL0144.
DR   PIR; JL0145; JL0145.
DR   RefSeq; NP_034689.2; NM_010559.3.
DR   AlphaFoldDB; P22272; -.
DR   SMR; P22272; -.
DR   IntAct; P22272; 1.
DR   STRING; 10090.ENSMUSP00000029559; -.
DR   GlyCosmos; P22272; 4 sites, No reported glycans.
DR   GlyGen; P22272; 4 sites.
DR   PhosphoSitePlus; P22272; -.
DR   MaxQB; P22272; -.
DR   PaxDb; 10090-ENSMUSP00000029559; -.
DR   ProteomicsDB; 267126; -.
DR   ABCD; P22272; 22 sequenced antibodies.
DR   Antibodypedia; 20397; 1173 antibodies from 43 providers.
DR   DNASU; 16194; -.
DR   Ensembl; ENSMUST00000029559.7; ENSMUSP00000029559.7; ENSMUSG00000027947.12.
DR   GeneID; 16194; -.
DR   KEGG; mmu:16194; -.
DR   UCSC; uc008qaf.1; mouse.
DR   AGR; MGI:105304; -.
DR   CTD; 16194; -.
DR   MGI; MGI:105304; Il6ra.
DR   VEuPathDB; HostDB:ENSMUSG00000027947; -.
DR   eggNOG; ENOG502RY0M; Eukaryota.
DR   GeneTree; ENSGT00940000161919; -.
DR   HOGENOM; CLU_051451_0_0_1; -.
DR   InParanoid; P22272; -.
DR   OMA; HDAWRGM; -.
DR   OrthoDB; 5363020at2759; -.
DR   PhylomeDB; P22272; -.
DR   TreeFam; TF331210; -.
DR   Reactome; R-MMU-1059683; Interleukin-6 signaling.
DR   Reactome; R-MMU-110056; MAPK3 (ERK1) activation.
DR   Reactome; R-MMU-112411; MAPK1 (ERK2) activation.
DR   BioGRID-ORCS; 16194; 3 hits in 79 CRISPR screens.
DR   PRO; PR:P22272; -.
DR   Proteomes; UP000000589; Chromosome 3.
DR   RNAct; P22272; Protein.
DR   Bgee; ENSMUSG00000027947; Expressed in granulocyte and 121 other cell types or tissues.
DR   ExpressionAtlas; P22272; baseline and differential.
DR   GO; GO:0016324; C:apical plasma membrane; ISO:MGI.
DR   GO; GO:0070110; C:ciliary neurotrophic factor receptor complex; ISO:MGI.
DR   GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR   GO; GO:0005576; C:extracellular region; ISO:MGI.
DR   GO; GO:0005615; C:extracellular space; ISO:MGI.
DR   GO; GO:0005896; C:interleukin-6 receptor complex; IDA:UniProtKB.
DR   GO; GO:0032809; C:neuronal cell body membrane; ISO:MGI.
DR   GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR   GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR   GO; GO:0070119; F:ciliary neurotrophic factor binding; ISO:MGI.
DR   GO; GO:0004897; F:ciliary neurotrophic factor receptor activity; IEA:Ensembl.
DR   GO; GO:0004896; F:cytokine receptor activity; ISO:MGI.
DR   GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR   GO; GO:0019970; F:interleukin-11 binding; IBA:GO_Central.
DR   GO; GO:0004921; F:interleukin-11 receptor activity; IBA:GO_Central.
DR   GO; GO:0019981; F:interleukin-6 binding; ISO:MGI.
DR   GO; GO:0004915; F:interleukin-6 receptor activity; IDA:UniProtKB.
DR   GO; GO:0005138; F:interleukin-6 receptor binding; IEA:Ensembl.
DR   GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR   GO; GO:0070120; P:ciliary neurotrophic factor-mediated signaling pathway; ISO:MGI.
DR   GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:MGI.
DR   GO; GO:0048589; P:developmental growth; ISO:MGI.
DR   GO; GO:0031018; P:endocrine pancreas development; ISO:MGI.
DR   GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IDA:UniProtKB.
DR   GO; GO:0032966; P:negative regulation of collagen biosynthetic process; ISO:MGI.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR   GO; GO:0032722; P:positive regulation of chemokine production; ISO:MGI.
DR   GO; GO:0072126; P:positive regulation of glomerular mesangial cell proliferation; ISO:MGI.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; ISO:MGI.
DR   GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:MGI.
DR   GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:MGI.
DR   GO; GO:1901731; P:positive regulation of platelet aggregation; ISO:MGI.
DR   GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:MGI.
DR   GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISO:MGI.
DR   GO; GO:0034097; P:response to cytokine; ISO:MGI.
DR   GO; GO:0072540; P:T-helper 17 cell lineage commitment; IDA:UniProtKB.
DR   GO; GO:0010573; P:vascular endothelial growth factor production; ISS:UniProtKB.
DR   CDD; cd00063; FN3; 1.
DR   CDD; cd20939; IgC2_D1_IL-6RA; 1.
DR   Gene3D; 2.60.40.10; Immunoglobulins; 3.
DR   InterPro; IPR003961; FN3_dom.
DR   InterPro; IPR036116; FN3_sf.
DR   InterPro; IPR003530; Hematopoietin_rcpt_L_F3_CS.
DR   InterPro; IPR007110; Ig-like_dom.
DR   InterPro; IPR036179; Ig-like_dom_sf.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR003599; Ig_sub.
DR   InterPro; IPR003598; Ig_sub2.
DR   InterPro; IPR013151; Immunoglobulin.
DR   InterPro; IPR015321; TypeI_recpt_CBD.
DR   PANTHER; PTHR23036; CYTOKINE RECEPTOR; 1.
DR   PANTHER; PTHR23036:SF98; INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA; 1.
DR   Pfam; PF00047; ig; 1.
DR   Pfam; PF09240; IL6Ra-bind; 1.
DR   SMART; SM00409; IG; 1.
DR   SMART; SM00408; IGc2; 1.
DR   SUPFAM; SSF49265; Fibronectin type III; 2.
DR   SUPFAM; SSF48726; Immunoglobulin; 1.
DR   PROSITE; PS50853; FN3; 2.
DR   PROSITE; PS01354; HEMATOPO_REC_L_F3; 1.
DR   PROSITE; PS50835; IG_LIKE; 1.
DR   Genevisible; P22272; MM.
PE   1: Evidence at protein level;
KW   Cell membrane; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW   Membrane; Receptor; Reference proteome; Repeat; Secreted; Signal;
KW   Transmembrane; Transmembrane helix.
FT   SIGNAL          1..19
FT   CHAIN           20..460
FT                   /note="Interleukin-6 receptor subunit alpha"
FT                   /id="PRO_0000010896"
FT   CHAIN           20..354
FT                   /note="Soluble interleukin-6 receptor subunit alpha"
FT                   /evidence="ECO:0000250|UniProtKB:P08887"
FT                   /id="PRO_0000450731"
FT   TOPO_DOM        20..364
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        365..385
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        386..460
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          20..116
FT                   /note="Ig-like C2-type"
FT   DOMAIN          109..214
FT                   /note="Fibronectin type-III 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT   DOMAIN          215..313
FT                   /note="Fibronectin type-III 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT   MOTIF           300..304
FT                   /note="WSXWS motif"
FT   SITE            354..355
FT                   /note="Cleavage; by ADAM10 and ADAM17"
FT                   /evidence="ECO:0000250|UniProtKB:P08887"
FT   CARBOHYD        32
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        55
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:P08887"
FT   CARBOHYD        150
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        218
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:P08887"
FT   DISULFID        25..190
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT   DISULFID        47..92
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT   DISULFID        117..128
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT   DISULFID        162..173
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT   CONFLICT        374
FT                   /note="A -> R (in Ref. 2; CAA37810)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   460 AA;  50455 MW;  F85C5906D08525C4 CRC64;
     MLTVGCTLLV ALLAAPAVAL VLGSCRALEV ANGTVTSLPG ATVTLICPGK EAAGNVTIHW
     VYSGSQNREW TTTGNTLVLR DVQLSDTGDY LCSLNDHLVG TVPLLVDVPP EEPKLSCFRK
     NPLVNAICEW RPSSTPSPTT KAVLFAKKIN TTNGKSDFQV PCQYSQQLKS FSCQVEILEG
     DKVYHIVSLC VANSVGSKSS HNEAFHSLKM VQPDPPANLV VSAIPGRPRW LKVSWQHPET
     WDPSYYLLQF QLRYRPVWSK EFTVLLLPVA QYQCVIHDAL RGVKHVVQVR GKEELDLGQW
     SEWSPEVTGT PWIAEPRTTP AGILWNPTQV SVEDSANHED QYESSTEATS VLAPVQESSS
     MSLPTFLVAG GSLAFGLLLC VFIILRLKQK WKSEAEKESK TTSPPPPPYS LGPLKPTFLL
     VPLLTPHSSG SDNTVNHSCL GVRDAQSPYD NSNRDYLFPR
//