SPNS2_MOUSE
ID SPNS2_MOUSE Reviewed; 549 AA.
AC Q91VM4; B9A1T4; Q5F242; Q8R119;
DT 02-OCT-2007, integrated into UniProtKB/Swiss-Prot.
DT 02-OCT-2007, sequence version 2.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=Sphingosine-1-phosphate transporter SPNS2 {ECO:0000305};
DE AltName: Full=Protein spinster homolog 2 {ECO:0000305};
DE AltName: Full=Spinster homolog 2 {ECO:0000303|PubMed:22664872};
DE Short=Spns2 {ECO:0000303|PubMed:22664872};
GN Name=Spns2 {ECO:0000303|PubMed:19074308, ECO:0000312|MGI:MGI:2384936};
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 [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=129, and FVB/N; TISSUE=Liver, and Mammary tumor;
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 2-549 (ISOFORM 1).
RX PubMed=19074308; DOI=10.1126/science.1167449;
RA Kawahara A., Nishi T., Hisano Y., Fukui H., Yamaguchi A., Mochizuki N.;
RT "The sphingolipid transporter spns2 functions in migration of zebrafish
RT myocardial precursors.";
RL Science 323:524-527(2009).
RN [4]
RP DISRUPTION PHENOTYPE, FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=22664872; DOI=10.4049/jimmunol.1200282;
RG Sanger Mouse Genetics Project;
RA Nijnik A., Clare S., Hale C., Chen J., Raisen C., Mottram L., Lucas M.,
RA Estabel J., Ryder E., Adissu H., Adams N.C., Ramirez-Solis R., White J.K.,
RA Steel K.P., Dougan G., Hancock R.E.;
RT "The role of sphingosine-1-phosphate transporter Spns2 in immune system
RT function.";
RL J. Immunol. 189:102-111(2012).
RN [5]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=23103166; DOI=10.1016/j.celrep.2012.09.021;
RA Mendoza A., Breart B., Ramos-Perez W.D., Pitt L.A., Gobert M., Sunkara M.,
RA Lafaille J.J., Morris A.J., Schwab S.R.;
RT "The transporter Spns2 is required for secretion of lymph but not plasma
RT sphingosine-1-phosphate.";
RL Cell Rep. 2:1104-1110(2012).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND DISRUPTION PHENOTYPE.
RX PubMed=22406534; DOI=10.1172/jci60746;
RA Fukuhara S., Simmons S., Kawamura S., Inoue A., Orba Y., Tokudome T.,
RA Sunden Y., Arai Y., Moriwaki K., Ishida J., Uemura A., Kiyonari H., Abe T.,
RA Fukamizu A., Hirashima M., Sawa H., Aoki J., Ishii M., Mochizuki N.;
RT "The sphingosine-1-phosphate transporter Spns2 expressed on endothelial
RT cells regulates lymphocyte trafficking in mice.";
RL J. Clin. Invest. 122:1416-1426(2012).
RN [7]
RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND
RP FUNCTION.
RX PubMed=23180825; DOI=10.1096/fj.12-219618;
RA Nagahashi M., Kim E.Y., Yamada A., Ramachandran S., Allegood J.C.,
RA Hait N.C., Maceyka M., Milstien S., Takabe K., Spiegel S.;
RT "Spns2, a transporter of phosphorylated sphingoid bases, regulates their
RT blood and lymph levels, and the lymphatic network.";
RL FASEB J. 27:1001-1011(2013).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=25356849; DOI=10.1371/journal.pgen.1004688;
RA Chen J., Ingham N., Kelly J., Jadeja S., Goulding D., Pass J.,
RA Mahajan V.B., Tsang S.H., Nijnik A., Jackson I.J., White J.K., Forge A.,
RA Jagger D., Steel K.P.;
RT "Spinster homolog 2 (spns2) deficiency causes early onset progressive
RT hearing loss.";
RL PLoS Genet. 10:e1004688-e1004688(2014).
RN [9]
RP DISRUPTION PHENOTYPE.
RX PubMed=30973865; DOI=10.1371/journal.pbio.3000194;
RA Ingham N.J., Pearson S.A., Vancollie V.E., Rook V., Lewis M.A., Chen J.,
RA Buniello A., Martelletti E., Preite L., Lam C.C., Weiss F.D., Powis Z.,
RA Suwannarat P., Lelliott C.J., Dawson S.J., White J.K., Steel K.P.;
RT "Mouse screen reveals multiple new genes underlying mouse and human hearing
RT loss.";
RL PLoS Biol. 17:E3000194-E3000194(2019).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=34260944; DOI=10.1016/j.celrep.2021.109368;
RA Okuniewska M., Fang V., Baeyens A., Raghavan V., Lee J.Y., Littman D.R.,
RA Schwab S.R.;
RT "SPNS2 enables T cell egress from lymph nodes during an immune response.";
RL Cell Rep. 36:109368-109368(2021).
RN [11]
RP FUNCTION.
RX PubMed=33785361; DOI=10.1016/j.jbc.2021.100605;
RA Goto H., Miyamoto M., Kihara A.;
RT "Direct uptake of sphingosine-1-phosphate independent of phospholipid
RT phosphatases.";
RL J. Biol. Chem. 296:100605-100605(2021).
CC -!- FUNCTION: Lipid transporter that specifically mediates export of
CC sphingosine-1-phosphate (sphing-4-enine 1-phosphate, S1P) and
CC sphinganine-1-phosphate in the lymph, thereby playing a role in
CC lymphocyte trafficking (PubMed:22664872, PubMed:23103166,
CC PubMed:22406534, PubMed:23180825, PubMed:34260944). S1P is a bioactive
CC signaling molecule that regulates many physiological processes
CC important for the development and for the immune system
CC (PubMed:22664872, PubMed:23103166, PubMed:22406534, PubMed:23180825,
CC PubMed:34260944). Regulates levels of S1P and the S1P gradient that
CC exists between the high circulating concentrations of S1P and low
CC tissue levels that control lymphocyte trafficking (PubMed:22664872,
CC PubMed:22406534, PubMed:23180825, PubMed:34260944). Required for the
CC egress of T-cells from lymph nodes during an immune response by
CC mediating S1P secretion, which generates a gradient that enables
CC activated T-cells to access lymph (PubMed:22406534, PubMed:34260944).
CC Also required for the egress of immature B-cells from the bone marrow
CC (PubMed:22406534). In contrast, it does not mediate S1P release from
CC red blood cells (PubMed:23103166, PubMed:22406534). Involved in
CC auditory function: S1P release in the inner ear is required for
CC maintenance of the endocochlear potential in the cochlea
CC (PubMed:25356849). In addition to export, also able to mediate S1P
CC import (PubMed:33785361). {ECO:0000269|PubMed:22406534,
CC ECO:0000269|PubMed:22664872, ECO:0000269|PubMed:23103166,
CC ECO:0000269|PubMed:23180825, ECO:0000269|PubMed:25356849,
CC ECO:0000269|PubMed:33785361, ECO:0000269|PubMed:34260944}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=sphing-4-enine 1-phosphate(in) = sphing-4-enine 1-
CC phosphate(out); Xref=Rhea:RHEA:38667, ChEBI:CHEBI:60119;
CC Evidence={ECO:0000269|PubMed:23180825, ECO:0000305|PubMed:22406534};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=sphinganine 1-phosphate(in) = sphinganine 1-phosphate(out);
CC Xref=Rhea:RHEA:38671, ChEBI:CHEBI:57939;
CC Evidence={ECO:0000269|PubMed:23180825};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:A2SWM2};
CC Multi-pass membrane protein {ECO:0000255}. Endosome membrane
CC {ECO:0000250|UniProtKB:A2SWM2}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q91VM4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q91VM4-2; Sequence=VSP_036390, VSP_036391;
CC -!- TISSUE SPECIFICITY: Expression is high in the lungs and liver, low in
CC the lymph nodes, spleen and bone marrow, and very low but detectable in
CC the thymus (PubMed:22664872). Not expressed in red blood cells
CC (PubMed:23103166). Also expressed in the inner ear: expressed in the
CC cochlea, both in the lateral wall and organ of Corti (PubMed:25356849).
CC {ECO:0000269|PubMed:22664872, ECO:0000269|PubMed:23103166,
CC ECO:0000269|PubMed:25356849}.
CC -!- DISRUPTION PHENOTYPE: Deficient mice are viable, do not exhibit cardiac
CC defects or embryonic lethality, and are generally normal and fertile
CC (PubMed:22664872, PubMed:22406534). Deficient mice have decreased
CC levels of sphingosine 1-phosphate (S1P) and dihydro-S1P in blood,
CC accompanied by increases in very long chain ceramide species, and have
CC defective lymphocyte trafficking (PubMed:22664872, PubMed:22406534,
CC PubMed:23180825). S1P levels are increased in lymph from deficient mice
CC as well as in specific tissues, including lymph nodes, and interstitial
CC fluid (PubMed:23180825). Moreover, these mice have aberrant lymphatic
CC sinus that appeared collapsed, with reduced numbers of lymphocytes
CC (PubMed:23180825). Mice display marked accumulation of mature T-cells
CC in thymus and decreased numbers of peripheral T-cells in blood and
CC secondary lymphoid organs (PubMed:22406534, PubMed:34260944). Mature
CC recirculating B-cells are reduced in frequency in the bone marrow as
CC well as in blood and secondary lymphoid organs (PubMed:22406534). Mice
CC do not show defects in S1P release from blood cells (PubMed:22406534).
CC Knockout mice are protected against experimental autoimmune
CC encephalomyelitis (PubMed:34260944). Mutants also show a profound
CC hearing impairment, characterized by a progressive degeneration of
CC sensory hair cells in the organ of Corti (PubMed:25356849,
CC PubMed:30973865). Hearing loss is caused by a decline in the
CC endocochlear potential (PubMed:25356849). Conditional deletion in the
CC cochlea causes early onset progressive hearing loss (PubMed:25356849).
CC In contrast, hearing impairment is not observed in mice with targeted
CC deletion in red blood cells, platelets, lymphatic or vascular
CC endothelial cells (PubMed:25356849). {ECO:0000269|PubMed:22406534,
CC ECO:0000269|PubMed:22664872, ECO:0000269|PubMed:23180825,
CC ECO:0000269|PubMed:25356849, ECO:0000269|PubMed:30973865,
CC ECO:0000269|PubMed:34260944}.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily. Spinster (TC
CC 2.A.1.49) family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH11467.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={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; AL662812; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC011467; AAH11467.1; ALT_INIT; mRNA.
DR EMBL; BC025823; AAH25823.1; -; mRNA.
DR EMBL; AB441166; BAH15193.1; -; mRNA.
DR CCDS; CCDS48841.1; -. [Q91VM4-1]
DR RefSeq; NP_694700.2; NM_153060.3. [Q91VM4-1]
DR RefSeq; XP_017169949.1; XM_017314460.1. [Q91VM4-1]
DR AlphaFoldDB; Q91VM4; -.
DR SMR; Q91VM4; -.
DR STRING; 10090.ENSMUSP00000044418; -.
DR SwissLipids; SLP:000001139; -.
DR iPTMnet; Q91VM4; -.
DR PhosphoSitePlus; Q91VM4; -.
DR SwissPalm; Q91VM4; -.
DR MaxQB; Q91VM4; -.
DR PaxDb; Q91VM4; -.
DR PRIDE; Q91VM4; -.
DR ProteomicsDB; 258594; -. [Q91VM4-1]
DR ProteomicsDB; 258595; -. [Q91VM4-2]
DR Antibodypedia; 42673; 125 antibodies from 19 providers.
DR Ensembl; ENSMUST00000045303; ENSMUSP00000044418; ENSMUSG00000040447. [Q91VM4-1]
DR GeneID; 216892; -.
DR KEGG; mmu:216892; -.
DR UCSC; uc007jyz.3; mouse. [Q91VM4-1]
DR UCSC; uc007jza.1; mouse. [Q91VM4-2]
DR CTD; 124976; -.
DR MGI; MGI:2384936; Spns2.
DR VEuPathDB; HostDB:ENSMUSG00000040447; -.
DR eggNOG; KOG1330; Eukaryota.
DR GeneTree; ENSGT00390000005976; -.
DR HOGENOM; CLU_001265_5_12_1; -.
DR InParanoid; Q91VM4; -.
DR OMA; WYVVVIC; -.
DR OrthoDB; 891881at2759; -.
DR PhylomeDB; Q91VM4; -.
DR TreeFam; TF314395; -.
DR Reactome; R-MMU-1660661; Sphingolipid de novo biosynthesis.
DR BioGRID-ORCS; 216892; 2 hits in 69 CRISPR screens.
DR ChiTaRS; Spns2; mouse.
DR PRO; PR:Q91VM4; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q91VM4; protein.
DR Bgee; ENSMUSG00000040447; Expressed in esophagus and 239 other tissues.
DR ExpressionAtlas; Q91VM4; baseline and differential.
DR Genevisible; Q91VM4; MM.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0046624; F:sphingolipid transporter activity; IDA:UniProtKB.
DR GO; GO:0022857; F:transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0001782; P:B cell homeostasis; IMP:MGI.
DR GO; GO:0060348; P:bone development; IMP:MGI.
DR GO; GO:0006869; P:lipid transport; ISO:MGI.
DR GO; GO:0048535; P:lymph node development; IMP:MGI.
DR GO; GO:0002260; P:lymphocyte homeostasis; IMP:MGI.
DR GO; GO:0072676; P:lymphocyte migration; IMP:MGI.
DR GO; GO:0048073; P:regulation of eye pigmentation; IMP:MGI.
DR GO; GO:0002920; P:regulation of humoral immune response; IDA:UniProtKB.
DR GO; GO:2000404; P:regulation of T cell migration; IDA:UniProtKB.
DR GO; GO:0007605; P:sensory perception of sound; IMP:UniProtKB.
DR GO; GO:0006665; P:sphingolipid metabolic process; IMP:MGI.
DR GO; GO:0003376; P:sphingosine-1-phosphate receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0043029; P:T cell homeostasis; IMP:MGI.
DR CDD; cd17328; MFS_spinster_like; 1.
DR Gene3D; 1.20.1250.20; -; 1.
DR InterPro; IPR011701; MFS.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR044770; MFS_spinster-like.
DR InterPro; IPR036259; MFS_trans_sf.
DR PANTHER; PTHR23505; PTHR23505; 1.
DR Pfam; PF07690; MFS_1; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
DR PROSITE; PS50850; MFS; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Deafness; Endosome; Lipid transport;
KW Membrane; Non-syndromic deafness; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..549
FT /note="Sphingosine-1-phosphate transporter SPNS2"
FT /id="PRO_0000305044"
FT TRANSMEM 141..161
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 169..189
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 202..222
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 229..249
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 261..281
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 320..340
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 364..384
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 398..418
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 422..442
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 466..486
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 507..527
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 14..36
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 78..97
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1..431
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_036390"
FT VAR_SEQ 432..448
FT /note="GETLLFSNWAITADILM -> MSLVHGSSSPDLPFLLQ (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_036391"
SQ SEQUENCE 549 AA; 58196 MW; BE82D3254BA8C8C3 CRC64;
MMCLECASAA AGGAEEEEAD AERRRRRRGA QPGAGGSACC GARGVGGAGV VSADEEVQTL
SGSVRRVPSG LPSIPSTPGC AAAAKGPSAP QPKPASLGRG RGAAAAILSL GNVLNYLDRY
TVAGVLLDIQ QHFGVKDRGA GLLQSVFICS FMVAAPIFGY LGDRFNRKVI LSCGIFFWSA
VTFSSSFIPQ QYFWLLVLSR GLVGIGEASY STIAPTIIGD LFTKNTRTLM LSVFYFAIPL
GSGLGYITGS SVKQAAGDWH WALRVSPVLG MITGTLILIL VPATKRGHAD QLGGQLKART
SWLRDMKALI RNRSYVFSSL ATSAVSFATG ALGMWIPLYL HRAQVVQKTA ETCNSPPCGA
KDSLIFGAIT CFTGFLGVVT GAGATRWCRL RTQRADPLVC AVGMLGSAIF ICLIFVAAKT
SIVGAYICIF VGETLLFSNW AITADILMYV VIPTRRATAV ALQSFTSHLL GDAGSPYLIG
FISDLIRQST KDSPLWEFLS LGYALMLCPF VVVLGGMFFL ATALFFLSDR AKAEQQVNQL
VMPPASVKV
