Full text data of TNFSF14
TNFSF14
(HVEML, LIGHT)
[Confidence: low (only semi-automatic identification from reviews)]
Tumor necrosis factor ligand superfamily member 14 (Herpes virus entry mediator ligand; HVEM-L; Herpesvirus entry mediator ligand; CD258; Tumor necrosis factor ligand superfamily member 14, membrane form; Tumor necrosis factor ligand superfamily member 14, soluble form)
Tumor necrosis factor ligand superfamily member 14 (Herpes virus entry mediator ligand; HVEM-L; Herpesvirus entry mediator ligand; CD258; Tumor necrosis factor ligand superfamily member 14, membrane form; Tumor necrosis factor ligand superfamily member 14, soluble form)
UniProt
O43557
ID TNF14_HUMAN Reviewed; 240 AA.
AC O43557; A8K7M2; C9J5H4; O75476; Q6FHA1; Q8WVF8; Q96LD2;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-NOV-2010, sequence version 2.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Tumor necrosis factor ligand superfamily member 14;
DE AltName: Full=Herpes virus entry mediator ligand;
DE Short=HVEM-L;
DE Short=Herpesvirus entry mediator ligand;
DE AltName: CD_antigen=CD258;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 14, membrane form;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 14, soluble form;
GN Name=TNFSF14; Synonyms=HVEML, LIGHT; ORFNames=UNQ391/PRO726;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT GLU-214.
RX PubMed=9462508; DOI=10.1016/S1074-7613(00)80455-0;
RA Mauri D.N., Ebner R., Montgomery R.I., Kochel K.D., Cheung T.C.,
RA Yu G.-L., Ruben S., Murphy M., Eisenberg R.J., Cohen G.H., Spear P.G.,
RA Ware C.F.;
RT "LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are
RT ligands for herpesvirus entry mediator.";
RL Immunity 8:21-30(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION.
RC TISSUE=Liver;
RX PubMed=9765287; DOI=10.1074/jbc.273.42.27548;
RA Harrop J.A., McDonnell P.C., Brigham-Burke M., Lyn S.D., Minton J.,
RA Tan K.B., Dede K., Spampanato J., Silverman C., Hensley P.,
RA DiPrinzio R., Emery J.G., Deen K., Eichman C., Chabot-Fletcher M.,
RA Truneh A., Young P.R.;
RT "Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for
RT HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell
RT growth.";
RL J. Biol. Chem. 273:27548-27556(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PROTEOLYTIC PROCESSING, AND
RP VARIANT GLU-214.
RX PubMed=11673523;
RA Granger S.W., Butrovich K.D., Houshmand P., Edwards W.R., Ware C.F.;
RT "Genomic characterization of LIGHT reveals linkage to an immune
RT response locus on chromosome 19p13.3 and distinct isoforms generated
RT by alternate splicing or proteolysis.";
RL J. Immunol. 167:5122-5128(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLU-214.
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLU-214.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLU-214.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 83-240, GLYCOSYLATION AT
RP ASN-102, AND DISULFIDE BOND.
RG New York structural genomics research consortium (NYSGRC);
RT "Crystal structure of LIGHT.";
RL Submitted (MAY-2012) to the PDB data bank.
CC -!- FUNCTION: Cytokine that binds to TNFRSF3/LTBR. Binding to the
CC decoy receptor TNFRSF6B modulates its effects. Activates NFKB,
CC stimulates the proliferation of T-cells, and inhibits growth of
CC the adenocarcinoma HT-29. Acts as a receptor for Herpes simplex
CC virus.
CC -!- SUBUNIT: Homotrimer.
CC -!- INTERACTION:
CC Q92956:TNFRSF14; NbExp=2; IntAct=EBI-524131, EBI-1056653;
CC O95407:TNFRSF6B; NbExp=2; IntAct=EBI-524131, EBI-524171;
CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor ligand superfamily
CC member 14, membrane form: Cell membrane; Single-pass type II
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor ligand superfamily
CC member 14, soluble form: Secreted.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O43557-1; Sequence=Displayed;
CC Name=2; Synonyms=LIGHT delta-TM;
CC IsoId=O43557-2; Sequence=VSP_006452;
CC -!- TISSUE SPECIFICITY: Predominantly expressed in the spleen but also
CC found in the brain. Weakly expressed in peripheral lymphoid
CC tissues and in heart, placenta, liver, lung, appendix, and kidney,
CC and no expression seen in fetal tissues, endocrine glands, or
CC nonhematopoietic tumor lines.
CC -!- INDUCTION: Up-regulated after T-cell activation.
CC -!- PTM: N-glycosylated.
CC -!- PTM: The soluble form of isoform 1 derives from the membrane form
CC by proteolytic processing.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family.
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DR EMBL; AF036581; AAC39563.1; -; mRNA.
DR EMBL; AF064090; AAC25169.1; -; mRNA.
DR EMBL; AY028261; AAK26160.1; -; mRNA.
DR EMBL; AY358812; AAQ89171.1; -; mRNA.
DR EMBL; AK292037; BAF84726.1; -; mRNA.
DR EMBL; CR541854; CAG46652.1; -; mRNA.
DR EMBL; CR541871; CAG46669.1; -; mRNA.
DR EMBL; AC008760; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69072.1; -; Genomic_DNA.
DR RefSeq; NP_003798.2; NM_003807.3.
DR RefSeq; NP_742011.2; NM_172014.2.
DR RefSeq; XP_005259727.1; XM_005259670.1.
DR UniGene; Hs.129708; -.
DR PDB; 4EN0; X-ray; 2.59 A; A/B/C=83-240.
DR PDB; 4J6G; X-ray; 2.40 A; A/B=83-240.
DR PDB; 4KG8; X-ray; 2.25 A; A/B/C=83-240.
DR PDB; 4KGG; X-ray; 2.78 A; A/B=83-240.
DR PDB; 4KGQ; X-ray; 2.27 A; A/B=83-240.
DR PDBsum; 4EN0; -.
DR PDBsum; 4J6G; -.
DR PDBsum; 4KG8; -.
DR PDBsum; 4KGG; -.
DR PDBsum; 4KGQ; -.
DR ProteinModelPortal; O43557; -.
DR SMR; O43557; 93-240.
DR DIP; DIP-3016N; -.
DR IntAct; O43557; 3.
DR STRING; 9606.ENSP00000245912; -.
DR PaxDb; O43557; -.
DR PRIDE; O43557; -.
DR DNASU; 8740; -.
DR Ensembl; ENST00000245912; ENSP00000245912; ENSG00000125735.
DR Ensembl; ENST00000326176; ENSP00000326940; ENSG00000125735.
DR Ensembl; ENST00000599359; ENSP00000469049; ENSG00000125735.
DR GeneID; 8740; -.
DR KEGG; hsa:8740; -.
DR UCSC; uc002mfk.2; human.
DR CTD; 8740; -.
DR GeneCards; GC19M006663; -.
DR HGNC; HGNC:11930; TNFSF14.
DR HPA; HPA012700; -.
DR MIM; 604520; gene.
DR neXtProt; NX_O43557; -.
DR PharmGKB; PA36622; -.
DR eggNOG; NOG40950; -.
DR HOVERGEN; HBG061471; -.
DR InParanoid; O43557; -.
DR KO; K05477; -.
DR OMA; DGQTDIP; -.
DR OrthoDB; EOG7V4B0Q; -.
DR PhylomeDB; O43557; -.
DR GeneWiki; TNFSF14; -.
DR GenomeRNAi; 8740; -.
DR NextBio; 32787; -.
DR PRO; PR:O43557; -.
DR Bgee; O43557; -.
DR CleanEx; HS_TNFSF14; -.
DR Genevestigator; O43557; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0005102; F:receptor binding; TAS:ProtInc.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0006955; P:immune response; IEA:InterPro.
DR GO; GO:0008588; P:release of cytoplasmic sequestered NF-kappaB; IDA:UniProtKB.
DR GO; GO:0031295; P:T cell costimulation; IEA:Ensembl.
DR GO; GO:0043029; P:T cell homeostasis; NAS:UniProtKB.
DR GO; GO:0042098; P:T cell proliferation; NAS:UniProtKB.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR006053; TNF.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR Pfam; PF00229; TNF; 1.
DR PRINTS; PR01234; TNECROSISFCT.
DR SMART; SM00207; TNF; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS00251; TNF_1; FALSE_NEG.
DR PROSITE; PS50049; TNF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Cytokine; Cytoplasm; Disulfide bond; Glycoprotein; Membrane;
KW Polymorphism; Reference proteome; Secreted; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 240 Tumor necrosis factor ligand superfamily
FT member 14, membrane form.
FT /FTId=PRO_0000034532.
FT CHAIN ?83 240 Tumor necrosis factor ligand superfamily
FT member 14, soluble form.
FT /FTId=PRO_0000034533.
FT TOPO_DOM 1 37 Cytoplasmic (Potential).
FT TRANSMEM 38 58 Helical; Signal-anchor for type II
FT membrane protein; (Potential).
FT TOPO_DOM 59 240 Extracellular (Potential).
FT SITE 82 83 Cleavage (Potential).
FT CARBOHYD 102 102 N-linked (GlcNAc...).
FT DISULFID 154 187
FT VAR_SEQ 38 73 Missing (in isoform 2).
FT /FTId=VSP_006452.
FT VARIANT 32 32 S -> L (in dbSNP:rs2291667).
FT /FTId=VAR_027677.
FT VARIANT 120 120 L -> V (in dbSNP:rs17851606).
FT /FTId=VAR_027678.
FT VARIANT 214 214 K -> E (in dbSNP:rs344560).
FT /FTId=VAR_027679.
FT STRAND 95 102
FT STRAND 107 110
FT STRAND 113 115
FT STRAND 122 129
FT STRAND 132 137
FT STRAND 139 151
FT STRAND 162 169
FT STRAND 173 175
FT STRAND 177 184
FT HELIX 186 189
FT STRAND 197 209
FT STRAND 214 220
FT HELIX 222 224
FT STRAND 232 239
SQ SEQUENCE 240 AA; 26350 MW; 49D0B1870F390B39 CRC64;
MEESVVRPSV FVVDGQTDIP FTRLGRSHRR QSCSVARVGL GLLLLLMGAG LAVQGWFLLQ
LHWRLGEMVT RLPDGPAGSW EQLIQERRSH EVNPAAHLTG ANSSLTGSGG PLLWETQLGL
AFLRGLSYHD GALVVTKAGY YYIYSKVQLG GVGCPLGLAS TITHGLYKRT PRYPEELELL
VSQQSPCGRA TSSSRVWWDS SFLGGVVHLE AGEKVVVRVL DERLVRLRDG TRSYFGAFMV
//
ID TNF14_HUMAN Reviewed; 240 AA.
AC O43557; A8K7M2; C9J5H4; O75476; Q6FHA1; Q8WVF8; Q96LD2;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-NOV-2010, sequence version 2.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Tumor necrosis factor ligand superfamily member 14;
DE AltName: Full=Herpes virus entry mediator ligand;
DE Short=HVEM-L;
DE Short=Herpesvirus entry mediator ligand;
DE AltName: CD_antigen=CD258;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 14, membrane form;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 14, soluble form;
GN Name=TNFSF14; Synonyms=HVEML, LIGHT; ORFNames=UNQ391/PRO726;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT GLU-214.
RX PubMed=9462508; DOI=10.1016/S1074-7613(00)80455-0;
RA Mauri D.N., Ebner R., Montgomery R.I., Kochel K.D., Cheung T.C.,
RA Yu G.-L., Ruben S., Murphy M., Eisenberg R.J., Cohen G.H., Spear P.G.,
RA Ware C.F.;
RT "LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are
RT ligands for herpesvirus entry mediator.";
RL Immunity 8:21-30(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION.
RC TISSUE=Liver;
RX PubMed=9765287; DOI=10.1074/jbc.273.42.27548;
RA Harrop J.A., McDonnell P.C., Brigham-Burke M., Lyn S.D., Minton J.,
RA Tan K.B., Dede K., Spampanato J., Silverman C., Hensley P.,
RA DiPrinzio R., Emery J.G., Deen K., Eichman C., Chabot-Fletcher M.,
RA Truneh A., Young P.R.;
RT "Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for
RT HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell
RT growth.";
RL J. Biol. Chem. 273:27548-27556(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PROTEOLYTIC PROCESSING, AND
RP VARIANT GLU-214.
RX PubMed=11673523;
RA Granger S.W., Butrovich K.D., Houshmand P., Edwards W.R., Ware C.F.;
RT "Genomic characterization of LIGHT reveals linkage to an immune
RT response locus on chromosome 19p13.3 and distinct isoforms generated
RT by alternate splicing or proteolysis.";
RL J. Immunol. 167:5122-5128(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLU-214.
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLU-214.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLU-214.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 83-240, GLYCOSYLATION AT
RP ASN-102, AND DISULFIDE BOND.
RG New York structural genomics research consortium (NYSGRC);
RT "Crystal structure of LIGHT.";
RL Submitted (MAY-2012) to the PDB data bank.
CC -!- FUNCTION: Cytokine that binds to TNFRSF3/LTBR. Binding to the
CC decoy receptor TNFRSF6B modulates its effects. Activates NFKB,
CC stimulates the proliferation of T-cells, and inhibits growth of
CC the adenocarcinoma HT-29. Acts as a receptor for Herpes simplex
CC virus.
CC -!- SUBUNIT: Homotrimer.
CC -!- INTERACTION:
CC Q92956:TNFRSF14; NbExp=2; IntAct=EBI-524131, EBI-1056653;
CC O95407:TNFRSF6B; NbExp=2; IntAct=EBI-524131, EBI-524171;
CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor ligand superfamily
CC member 14, membrane form: Cell membrane; Single-pass type II
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor ligand superfamily
CC member 14, soluble form: Secreted.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O43557-1; Sequence=Displayed;
CC Name=2; Synonyms=LIGHT delta-TM;
CC IsoId=O43557-2; Sequence=VSP_006452;
CC -!- TISSUE SPECIFICITY: Predominantly expressed in the spleen but also
CC found in the brain. Weakly expressed in peripheral lymphoid
CC tissues and in heart, placenta, liver, lung, appendix, and kidney,
CC and no expression seen in fetal tissues, endocrine glands, or
CC nonhematopoietic tumor lines.
CC -!- INDUCTION: Up-regulated after T-cell activation.
CC -!- PTM: N-glycosylated.
CC -!- PTM: The soluble form of isoform 1 derives from the membrane form
CC by proteolytic processing.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF036581; AAC39563.1; -; mRNA.
DR EMBL; AF064090; AAC25169.1; -; mRNA.
DR EMBL; AY028261; AAK26160.1; -; mRNA.
DR EMBL; AY358812; AAQ89171.1; -; mRNA.
DR EMBL; AK292037; BAF84726.1; -; mRNA.
DR EMBL; CR541854; CAG46652.1; -; mRNA.
DR EMBL; CR541871; CAG46669.1; -; mRNA.
DR EMBL; AC008760; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69072.1; -; Genomic_DNA.
DR RefSeq; NP_003798.2; NM_003807.3.
DR RefSeq; NP_742011.2; NM_172014.2.
DR RefSeq; XP_005259727.1; XM_005259670.1.
DR UniGene; Hs.129708; -.
DR PDB; 4EN0; X-ray; 2.59 A; A/B/C=83-240.
DR PDB; 4J6G; X-ray; 2.40 A; A/B=83-240.
DR PDB; 4KG8; X-ray; 2.25 A; A/B/C=83-240.
DR PDB; 4KGG; X-ray; 2.78 A; A/B=83-240.
DR PDB; 4KGQ; X-ray; 2.27 A; A/B=83-240.
DR PDBsum; 4EN0; -.
DR PDBsum; 4J6G; -.
DR PDBsum; 4KG8; -.
DR PDBsum; 4KGG; -.
DR PDBsum; 4KGQ; -.
DR ProteinModelPortal; O43557; -.
DR SMR; O43557; 93-240.
DR DIP; DIP-3016N; -.
DR IntAct; O43557; 3.
DR STRING; 9606.ENSP00000245912; -.
DR PaxDb; O43557; -.
DR PRIDE; O43557; -.
DR DNASU; 8740; -.
DR Ensembl; ENST00000245912; ENSP00000245912; ENSG00000125735.
DR Ensembl; ENST00000326176; ENSP00000326940; ENSG00000125735.
DR Ensembl; ENST00000599359; ENSP00000469049; ENSG00000125735.
DR GeneID; 8740; -.
DR KEGG; hsa:8740; -.
DR UCSC; uc002mfk.2; human.
DR CTD; 8740; -.
DR GeneCards; GC19M006663; -.
DR HGNC; HGNC:11930; TNFSF14.
DR HPA; HPA012700; -.
DR MIM; 604520; gene.
DR neXtProt; NX_O43557; -.
DR PharmGKB; PA36622; -.
DR eggNOG; NOG40950; -.
DR HOVERGEN; HBG061471; -.
DR InParanoid; O43557; -.
DR KO; K05477; -.
DR OMA; DGQTDIP; -.
DR OrthoDB; EOG7V4B0Q; -.
DR PhylomeDB; O43557; -.
DR GeneWiki; TNFSF14; -.
DR GenomeRNAi; 8740; -.
DR NextBio; 32787; -.
DR PRO; PR:O43557; -.
DR Bgee; O43557; -.
DR CleanEx; HS_TNFSF14; -.
DR Genevestigator; O43557; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0005102; F:receptor binding; TAS:ProtInc.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0006955; P:immune response; IEA:InterPro.
DR GO; GO:0008588; P:release of cytoplasmic sequestered NF-kappaB; IDA:UniProtKB.
DR GO; GO:0031295; P:T cell costimulation; IEA:Ensembl.
DR GO; GO:0043029; P:T cell homeostasis; NAS:UniProtKB.
DR GO; GO:0042098; P:T cell proliferation; NAS:UniProtKB.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR006053; TNF.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR Pfam; PF00229; TNF; 1.
DR PRINTS; PR01234; TNECROSISFCT.
DR SMART; SM00207; TNF; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS00251; TNF_1; FALSE_NEG.
DR PROSITE; PS50049; TNF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Cytokine; Cytoplasm; Disulfide bond; Glycoprotein; Membrane;
KW Polymorphism; Reference proteome; Secreted; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 240 Tumor necrosis factor ligand superfamily
FT member 14, membrane form.
FT /FTId=PRO_0000034532.
FT CHAIN ?83 240 Tumor necrosis factor ligand superfamily
FT member 14, soluble form.
FT /FTId=PRO_0000034533.
FT TOPO_DOM 1 37 Cytoplasmic (Potential).
FT TRANSMEM 38 58 Helical; Signal-anchor for type II
FT membrane protein; (Potential).
FT TOPO_DOM 59 240 Extracellular (Potential).
FT SITE 82 83 Cleavage (Potential).
FT CARBOHYD 102 102 N-linked (GlcNAc...).
FT DISULFID 154 187
FT VAR_SEQ 38 73 Missing (in isoform 2).
FT /FTId=VSP_006452.
FT VARIANT 32 32 S -> L (in dbSNP:rs2291667).
FT /FTId=VAR_027677.
FT VARIANT 120 120 L -> V (in dbSNP:rs17851606).
FT /FTId=VAR_027678.
FT VARIANT 214 214 K -> E (in dbSNP:rs344560).
FT /FTId=VAR_027679.
FT STRAND 95 102
FT STRAND 107 110
FT STRAND 113 115
FT STRAND 122 129
FT STRAND 132 137
FT STRAND 139 151
FT STRAND 162 169
FT STRAND 173 175
FT STRAND 177 184
FT HELIX 186 189
FT STRAND 197 209
FT STRAND 214 220
FT HELIX 222 224
FT STRAND 232 239
SQ SEQUENCE 240 AA; 26350 MW; 49D0B1870F390B39 CRC64;
MEESVVRPSV FVVDGQTDIP FTRLGRSHRR QSCSVARVGL GLLLLLMGAG LAVQGWFLLQ
LHWRLGEMVT RLPDGPAGSW EQLIQERRSH EVNPAAHLTG ANSSLTGSGG PLLWETQLGL
AFLRGLSYHD GALVVTKAGY YYIYSKVQLG GVGCPLGLAS TITHGLYKRT PRYPEELELL
VSQQSPCGRA TSSSRVWWDS SFLGGVVHLE AGEKVVVRVL DERLVRLRDG TRSYFGAFMV
//
MIM
604520
*RECORD*
*FIELD* NO
604520
*FIELD* TI
*604520 TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 14; TNFSF14
;;LIGHT;;
HERPESVIRUS ENTRY MEDIATOR LIGAND; HVEML
read more*FIELD* TX
CLONING
Viruses gain entry into cells by means of receptors encoded by genes of
the host cell. Herpes simplex virus (HSV) has been shown to infect
cells, including activated T lymphocytes, by means of an HSV envelope
glycoprotein D attaching to the herpesvirus entry mediator (HVEM), a
member of the tumor necrosis factor receptor superfamily (TNFRSF14;
602746). By screening activated T cells by FACS for staining with a
surrogate receptor composed of the extracellular domain of HVEM and the
Fc of IgG (see 146790), Mauri et al. (1998) determined by competition
experiments that HVEM binds with secreted lymphotoxin A (LTA; 153440)
and a 29- to 30-kD protein that they designated LIGHT (for homologous to
lymphotoxins, exhibits inducible expression, and competes with HSV
glycoprotein D for HVEM, a receptor expressed by T lymphocytes). By
screening an activated T-cell library, they identified a LIGHT cDNA,
which encodes a 240-amino acid protein with a 37-amino acid N-terminal
cytosolic domain and a 22-amino acid type II transmembrane stretch. In
the C-terminal receptor-binding domain, LIGHT exhibits 34% identity with
lymphotoxin B (LTB; 600978) and 31% identity with FASL (TNFSF6; 134638)
and lesser identity with other TNFSFs. The residues with the greatest
homology are those forming the beta-strand scaffold. Northern blot
analysis revealed expression of a 2.5-kb transcript for LIGHT
predominantly in spleen but also in brain where a secondary 3.5-kb
transcript was seen. Weaker expression was detected in peripheral
lymphoid tissues and in heart, placenta, liver, lung, appendix, and
kidney, and no expression was detected in fetal tissues, endocrine
glands, or nonhematopoietic tumor lines.
By screening soluble forms of novel TNFSF proteins derived from an EST
database with an HVEM-FcIgG fusion protein, Harrop et al. (1998) also
identified TNFSF14, which they termed HVEML.
By RT-PCR analysis, Granger et al. (2001) detected a smaller LIGHT
transcript with an internal deletion of 36 amino acids that removes the
entire transmembrane domain of the type II glycoprotein.
Immunoprecipitation analysis showed cytosolic expression of a 28-kD
protein corresponding to this alternative transcript of LIGHT.
Glycosidase treatment and immunoprecipitation analysis indicated that
the full-length form of LIGHT, but not the shorter variant, is
glycosylated. A shed form of LIGHT was capable of binding HVEM but was
not capable of inducing apoptosis. Granger et al. (2001) concluded that
LIGHT exists in several molecular forms that are directed to the
extracellular space, the cell membrane, and cytosolic compartments.
GENE FUNCTION
Mauri et al. (1998) found that HSV entry into cells could be inhibited
by coexpression of HVEM with LIGHT or glycoprotein D1.
Harrop et al. (1998) determined that HVEML activates NFKB (see 164011),
stimulates proliferation of T cells, and inhibits growth of the
adenocarcinoma HT-29.
By flow cytometric and RT-PCR analysis, Morel et al. (2000) showed that
expression of LIGHT was upregulated, whereas HVEM expression was
downregulated, after T-cell activation, particularly CD8-positive T-cell
activation.
Nonantigenic stromal cells may act as a barrier to immunologic rejection
of tumors. Yu et al. (2004) forced expression of LIGHT in a mouse
fibrosarcoma line and observed a massive infiltration of naive T
lymphocytes that correlated with an upregulation of chemokine (e.g.,
CCL21; 602737) production and adhesion molecule (e.g., MADCAM1; 102670)
expression, both of which are regulated by lymphotoxin-beta receptor
(LTBR; 600979) signaling. The ensuing T-cell activation led to the
rejection of tumors at local and distal sites.
Lo et al. (2007) identified lymphotoxin (see 153440) and LIGHT, tumor
necrosis factor cytokine family members that are primarily expressed on
lymphocytes, as critical regulators of key enzymes that control lipid
metabolism. Dysregulation of LIGHT expression on T cells resulted in
hypertriglyceridemia and hypercholesterolemia. In low density
lipoprotein receptor (606945)-deficient mice, which lack the ability to
control lipid levels in the blood, inhibition of lymphotoxin and LIGHT
signaling with a soluble LTBR decoy protein attenuated the dyslipidemia.
Lo et al. (2007) concluded that the immune system directly influences
lipid metabolism and that lymphotoxin modulating agents may represent a
novel therapeutic route for the treatment of dyslipidemia.
GENE STRUCTURE
By genomic sequence analysis, Granger et al. (2001) determined that from
AUG to the stop codon the TNFSF14 gene spans 5.1 kb and contains 4
exons. Exon 4 encodes the receptor-binding domain and includes a site
for N-linked glycosylation (asn102).
MAPPING
By genomic sequence and FISH analyses, Granger et al. (2001) mapped the
TNFSF14 gene to chromosome 19p13.3, telomeric to and 7.8 kb from the C3
gene (120700), centromeric to and within 79 kb of the CD70 gene (TNFSF7;
602840), and centromeric to and 235 kb from the 4-1BBL gene (TNFSF9;
606182). The authors noted that along with 1q21-q25, 1p32-p11, and
9q33-q34, chromosome 19p13.3-p13.1 is paralogous to the MHC region on
chromosome 6; all of these regions contain TNFSF members.
ANIMAL MODEL
To investigate T-cell involvement in IgA nephropathy (161950), Wang et
al. (2004) examined a murine model that spontaneously develops T
cell-mediated intestinal inflammation accompanied by pathologic features
similar to those of human IgA nephropathy. Intestinal inflammation
mediated by Tnfsf14, which is a ligand for Ltbr, not only stimulated IgA
overproduction in the gut but also resulted in defective IgA
transportation into the gut lumen, causing a dramatic increase in serum
polymeric IgA. Engagement of Ltbr by Tnfsf14 was essential for both
intestinal inflammation and hyperserum IgA syndrome in this model. Wang
et al. (2004) found increased IgA-producing cells in the gut, elevated
serum IgA levels, and severe hematuria in a majority of patients with
inflammatory bowel disease (see IBD1; 266600), either Crohn disease (CD)
or ulcerative colitis (UC). The authors concluded that dysregulated
TNFSF14 expression and intestinal inflammation are critical to the
pathogenesis of IgA nephropathy.
Wang et al. (2005) found that adoptive transfer of Hvem-expressing
mesenteric lymph node cells from mice transgenic for Light into Rag1
(179615) -/- mice, but not into Ltbr -/- mice, resulted in consistent
and rapid development of experimental Crohn disease. These mice
displayed key pathologic features of CD, including fissuring ulcers and
ileitis, and expressed Th1-type cytokines consistent with the cytokine
profile observed in CD patients. Real-time PCR analysis detected
upregulated expression of LIGHT in humans with active CD, as well as in
humans with ulcerative colitis. Wang et al. (2005) concluded that LIGHT
expression drives the activation and expansion of Th1 cells in the
intestine in CD and requires both HVEM and LTBR.
By challenging mice with extracts of house dust mite allergen, Doherty
et al. (2011) demonstrated expression of Light on lung inflammatory
cells. Inhibiting Light expression with an Ltbr-Fc fusion protein
reduced lung fibrosis, smooth muscle hyperplasia, and airway
hyperresponsiveness, but not airway eosinophilia, in mouse models of
chronic asthma. Mice lacking Light had impaired fibrosis and smooth
muscle accumulation. Blockade of Light suppressed lung expression of
Tgfb (190180) and Il13 (147683), which are implicated in allergy and
lung remodeling in humans. Exogenous administration of Light to airways
induced fibrosis and smooth muscle hyperplasia. Doherty et al. (2011)
concluded that LIGHT may be a target to prevent asthma-related airway
remodeling.
*FIELD* RF
1. Doherty, T. A.; Soroosh, P.; Khorram, N.; Fukuyama, S.; Rosenthal,
P.; Cho, J. Y.; Norris, P. S.; Choi, H.; Scheu, S.; Pfeffer, K.; Zuraw,
B. L.; Ware, C. F.; Broide, D. H.; Croft, M.: The tumor necrosis
factor family member LIGHT is a target for asthmatic airway remodeling. Nature
Med. 17: 596-603, 2011.
2. Granger, S. W.; Butrovich, K. D.; Houshmand, P.; Edwards, W. R.;
Ware, C. F.: Genomic characterization of LIGHT reveals linkage to
an immune response locus on chromosome 19p13.3 and distinct isoforms
generated by alternate splicing or proteolysis. J. Immun. 167: 5122-5128,
2001.
3. Harrop, J. A.; McDonnell, P. C.; Brigham-Burke, M.; Lyn, S. D.;
Minton, J.; Tan, K. B.; Dede, K.; Spampanato, J.; Silverman, C.;
Hensley, P.; DiPrinzio, R.; Emery, J. G.; Deen, K.; Eichman, C.; Chabot-Fletcher,
M.; Truneh, A.; Young, P. R.: Herpesvirus entry mediator ligand (HVEM-L),
a novel ligand for HVEM/TR2, stimulates proliferation of T cells and
inhibits HT29 cell growth. . J. Biol. Chem. 273: 27548-27556, 1998.
4. Lo, J. C.; Wang, Y.; Tumanov, A. V.; Bamji, M.; Yao, Z.; Reardon,
C. A.; Getz, G. S.; Fu, Y.-X.: Lymphotoxin beta receptor-dependent
control of lipid homeostasis. Science 316: 285-288, 2007.
5. Mauri, D. N.; Ebner, R.; Montgomery, R. I.; Kochel, K. D.; Cheung,
T. C.; Yu, G. L.; Ruben, S.; Murphy, M.; Eisenberg, R. J.; Cohen,
G. H.; Spear, P. G.; Ware, C. F.: LIGHT, a new member of the TNF
superfamily, and lymphotoxin alpha are ligands for herpesvirus entry
mediator. Immunity 8: 21-30, 1998.
6. Morel, Y.; Schiano de Colella, J.-M.; Harrop, J.; Deen, K. C.;
Holmes, S. D.; Wattam, T. A.; Khandekar, S. S.; Truneh, A.; Sweet,
R. W.; Gastaut, J.-A.; Olive, D.; Costello, R. T.: Reciprocal expression
of the TNF family receptor herpes virus entry mediator and its ligand
LIGHT on activated T cells: LIGHT down-regulates its own receptor. J.
Immun. 165: 4397-4404, 2000.
7. Wang, J.; Anders, R. A.; Wang, Y.; Turner, J. R.; Abraham, C.;
Pfeffer, K.; Fu, Y.-X.: The critical role of LIGHT in promoting intestinal
inflammation and Crohn's disease. J. Immun. 174: 8173-8182, 2005.
8. Wang, J.; Anders, R. A.; Wu, Q.; Peng, D.; Cho, J. H.; Sun, Y.;
Karaliukas, R.; Kang, H.-S.; Turner, J. R.; Fu, Y.-X.: Dysregulated
LIGHT expression on T cells mediates intestinal inflammation and contributes
to IgA nephropathy. J. Clin. Invest. 113: 826-835, 2004.
9. Yu, P.; Lee, Y.; Liu, W.; Chin, R. K.; Wang, J.; Wang, Y.; Schietinger,
A.; Philip, M.; Schreiber, H.; Fu, Y.-X.: Priming of naive T cells
inside tumors leads to eradication of established tumors. Nature
Immun. 5: 141-149, 2004.
*FIELD* CN
Paul J. Converse - updated: 5/12/2011
Ada Hamosh - updated: 6/4/2007
Paul J. Converse - updated: 11/1/2006
Marla J. F. O'Neill - updated: 5/20/2004
Paul J. Converse - updated: 5/5/2004
Paul J. Converse - updated: 12/11/2001
Paul J. Converse - updated: 11/22/2000
*FIELD* CD
Paul J. Converse: 2/8/2000
*FIELD* ED
mgross: 05/13/2011
terry: 5/12/2011
carol: 8/14/2008
alopez: 6/18/2007
terry: 6/4/2007
mgross: 11/7/2006
terry: 11/1/2006
carol: 5/24/2004
terry: 5/20/2004
mgross: 5/5/2004
mgross: 2/22/2002
mgross: 1/9/2002
mgross: 1/8/2002
terry: 12/11/2001
mgross: 11/22/2000
carol: 11/1/2000
carol: 2/10/2000
carol: 2/9/2000
*RECORD*
*FIELD* NO
604520
*FIELD* TI
*604520 TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 14; TNFSF14
;;LIGHT;;
HERPESVIRUS ENTRY MEDIATOR LIGAND; HVEML
read more*FIELD* TX
CLONING
Viruses gain entry into cells by means of receptors encoded by genes of
the host cell. Herpes simplex virus (HSV) has been shown to infect
cells, including activated T lymphocytes, by means of an HSV envelope
glycoprotein D attaching to the herpesvirus entry mediator (HVEM), a
member of the tumor necrosis factor receptor superfamily (TNFRSF14;
602746). By screening activated T cells by FACS for staining with a
surrogate receptor composed of the extracellular domain of HVEM and the
Fc of IgG (see 146790), Mauri et al. (1998) determined by competition
experiments that HVEM binds with secreted lymphotoxin A (LTA; 153440)
and a 29- to 30-kD protein that they designated LIGHT (for homologous to
lymphotoxins, exhibits inducible expression, and competes with HSV
glycoprotein D for HVEM, a receptor expressed by T lymphocytes). By
screening an activated T-cell library, they identified a LIGHT cDNA,
which encodes a 240-amino acid protein with a 37-amino acid N-terminal
cytosolic domain and a 22-amino acid type II transmembrane stretch. In
the C-terminal receptor-binding domain, LIGHT exhibits 34% identity with
lymphotoxin B (LTB; 600978) and 31% identity with FASL (TNFSF6; 134638)
and lesser identity with other TNFSFs. The residues with the greatest
homology are those forming the beta-strand scaffold. Northern blot
analysis revealed expression of a 2.5-kb transcript for LIGHT
predominantly in spleen but also in brain where a secondary 3.5-kb
transcript was seen. Weaker expression was detected in peripheral
lymphoid tissues and in heart, placenta, liver, lung, appendix, and
kidney, and no expression was detected in fetal tissues, endocrine
glands, or nonhematopoietic tumor lines.
By screening soluble forms of novel TNFSF proteins derived from an EST
database with an HVEM-FcIgG fusion protein, Harrop et al. (1998) also
identified TNFSF14, which they termed HVEML.
By RT-PCR analysis, Granger et al. (2001) detected a smaller LIGHT
transcript with an internal deletion of 36 amino acids that removes the
entire transmembrane domain of the type II glycoprotein.
Immunoprecipitation analysis showed cytosolic expression of a 28-kD
protein corresponding to this alternative transcript of LIGHT.
Glycosidase treatment and immunoprecipitation analysis indicated that
the full-length form of LIGHT, but not the shorter variant, is
glycosylated. A shed form of LIGHT was capable of binding HVEM but was
not capable of inducing apoptosis. Granger et al. (2001) concluded that
LIGHT exists in several molecular forms that are directed to the
extracellular space, the cell membrane, and cytosolic compartments.
GENE FUNCTION
Mauri et al. (1998) found that HSV entry into cells could be inhibited
by coexpression of HVEM with LIGHT or glycoprotein D1.
Harrop et al. (1998) determined that HVEML activates NFKB (see 164011),
stimulates proliferation of T cells, and inhibits growth of the
adenocarcinoma HT-29.
By flow cytometric and RT-PCR analysis, Morel et al. (2000) showed that
expression of LIGHT was upregulated, whereas HVEM expression was
downregulated, after T-cell activation, particularly CD8-positive T-cell
activation.
Nonantigenic stromal cells may act as a barrier to immunologic rejection
of tumors. Yu et al. (2004) forced expression of LIGHT in a mouse
fibrosarcoma line and observed a massive infiltration of naive T
lymphocytes that correlated with an upregulation of chemokine (e.g.,
CCL21; 602737) production and adhesion molecule (e.g., MADCAM1; 102670)
expression, both of which are regulated by lymphotoxin-beta receptor
(LTBR; 600979) signaling. The ensuing T-cell activation led to the
rejection of tumors at local and distal sites.
Lo et al. (2007) identified lymphotoxin (see 153440) and LIGHT, tumor
necrosis factor cytokine family members that are primarily expressed on
lymphocytes, as critical regulators of key enzymes that control lipid
metabolism. Dysregulation of LIGHT expression on T cells resulted in
hypertriglyceridemia and hypercholesterolemia. In low density
lipoprotein receptor (606945)-deficient mice, which lack the ability to
control lipid levels in the blood, inhibition of lymphotoxin and LIGHT
signaling with a soluble LTBR decoy protein attenuated the dyslipidemia.
Lo et al. (2007) concluded that the immune system directly influences
lipid metabolism and that lymphotoxin modulating agents may represent a
novel therapeutic route for the treatment of dyslipidemia.
GENE STRUCTURE
By genomic sequence analysis, Granger et al. (2001) determined that from
AUG to the stop codon the TNFSF14 gene spans 5.1 kb and contains 4
exons. Exon 4 encodes the receptor-binding domain and includes a site
for N-linked glycosylation (asn102).
MAPPING
By genomic sequence and FISH analyses, Granger et al. (2001) mapped the
TNFSF14 gene to chromosome 19p13.3, telomeric to and 7.8 kb from the C3
gene (120700), centromeric to and within 79 kb of the CD70 gene (TNFSF7;
602840), and centromeric to and 235 kb from the 4-1BBL gene (TNFSF9;
606182). The authors noted that along with 1q21-q25, 1p32-p11, and
9q33-q34, chromosome 19p13.3-p13.1 is paralogous to the MHC region on
chromosome 6; all of these regions contain TNFSF members.
ANIMAL MODEL
To investigate T-cell involvement in IgA nephropathy (161950), Wang et
al. (2004) examined a murine model that spontaneously develops T
cell-mediated intestinal inflammation accompanied by pathologic features
similar to those of human IgA nephropathy. Intestinal inflammation
mediated by Tnfsf14, which is a ligand for Ltbr, not only stimulated IgA
overproduction in the gut but also resulted in defective IgA
transportation into the gut lumen, causing a dramatic increase in serum
polymeric IgA. Engagement of Ltbr by Tnfsf14 was essential for both
intestinal inflammation and hyperserum IgA syndrome in this model. Wang
et al. (2004) found increased IgA-producing cells in the gut, elevated
serum IgA levels, and severe hematuria in a majority of patients with
inflammatory bowel disease (see IBD1; 266600), either Crohn disease (CD)
or ulcerative colitis (UC). The authors concluded that dysregulated
TNFSF14 expression and intestinal inflammation are critical to the
pathogenesis of IgA nephropathy.
Wang et al. (2005) found that adoptive transfer of Hvem-expressing
mesenteric lymph node cells from mice transgenic for Light into Rag1
(179615) -/- mice, but not into Ltbr -/- mice, resulted in consistent
and rapid development of experimental Crohn disease. These mice
displayed key pathologic features of CD, including fissuring ulcers and
ileitis, and expressed Th1-type cytokines consistent with the cytokine
profile observed in CD patients. Real-time PCR analysis detected
upregulated expression of LIGHT in humans with active CD, as well as in
humans with ulcerative colitis. Wang et al. (2005) concluded that LIGHT
expression drives the activation and expansion of Th1 cells in the
intestine in CD and requires both HVEM and LTBR.
By challenging mice with extracts of house dust mite allergen, Doherty
et al. (2011) demonstrated expression of Light on lung inflammatory
cells. Inhibiting Light expression with an Ltbr-Fc fusion protein
reduced lung fibrosis, smooth muscle hyperplasia, and airway
hyperresponsiveness, but not airway eosinophilia, in mouse models of
chronic asthma. Mice lacking Light had impaired fibrosis and smooth
muscle accumulation. Blockade of Light suppressed lung expression of
Tgfb (190180) and Il13 (147683), which are implicated in allergy and
lung remodeling in humans. Exogenous administration of Light to airways
induced fibrosis and smooth muscle hyperplasia. Doherty et al. (2011)
concluded that LIGHT may be a target to prevent asthma-related airway
remodeling.
*FIELD* RF
1. Doherty, T. A.; Soroosh, P.; Khorram, N.; Fukuyama, S.; Rosenthal,
P.; Cho, J. Y.; Norris, P. S.; Choi, H.; Scheu, S.; Pfeffer, K.; Zuraw,
B. L.; Ware, C. F.; Broide, D. H.; Croft, M.: The tumor necrosis
factor family member LIGHT is a target for asthmatic airway remodeling. Nature
Med. 17: 596-603, 2011.
2. Granger, S. W.; Butrovich, K. D.; Houshmand, P.; Edwards, W. R.;
Ware, C. F.: Genomic characterization of LIGHT reveals linkage to
an immune response locus on chromosome 19p13.3 and distinct isoforms
generated by alternate splicing or proteolysis. J. Immun. 167: 5122-5128,
2001.
3. Harrop, J. A.; McDonnell, P. C.; Brigham-Burke, M.; Lyn, S. D.;
Minton, J.; Tan, K. B.; Dede, K.; Spampanato, J.; Silverman, C.;
Hensley, P.; DiPrinzio, R.; Emery, J. G.; Deen, K.; Eichman, C.; Chabot-Fletcher,
M.; Truneh, A.; Young, P. R.: Herpesvirus entry mediator ligand (HVEM-L),
a novel ligand for HVEM/TR2, stimulates proliferation of T cells and
inhibits HT29 cell growth. . J. Biol. Chem. 273: 27548-27556, 1998.
4. Lo, J. C.; Wang, Y.; Tumanov, A. V.; Bamji, M.; Yao, Z.; Reardon,
C. A.; Getz, G. S.; Fu, Y.-X.: Lymphotoxin beta receptor-dependent
control of lipid homeostasis. Science 316: 285-288, 2007.
5. Mauri, D. N.; Ebner, R.; Montgomery, R. I.; Kochel, K. D.; Cheung,
T. C.; Yu, G. L.; Ruben, S.; Murphy, M.; Eisenberg, R. J.; Cohen,
G. H.; Spear, P. G.; Ware, C. F.: LIGHT, a new member of the TNF
superfamily, and lymphotoxin alpha are ligands for herpesvirus entry
mediator. Immunity 8: 21-30, 1998.
6. Morel, Y.; Schiano de Colella, J.-M.; Harrop, J.; Deen, K. C.;
Holmes, S. D.; Wattam, T. A.; Khandekar, S. S.; Truneh, A.; Sweet,
R. W.; Gastaut, J.-A.; Olive, D.; Costello, R. T.: Reciprocal expression
of the TNF family receptor herpes virus entry mediator and its ligand
LIGHT on activated T cells: LIGHT down-regulates its own receptor. J.
Immun. 165: 4397-4404, 2000.
7. Wang, J.; Anders, R. A.; Wang, Y.; Turner, J. R.; Abraham, C.;
Pfeffer, K.; Fu, Y.-X.: The critical role of LIGHT in promoting intestinal
inflammation and Crohn's disease. J. Immun. 174: 8173-8182, 2005.
8. Wang, J.; Anders, R. A.; Wu, Q.; Peng, D.; Cho, J. H.; Sun, Y.;
Karaliukas, R.; Kang, H.-S.; Turner, J. R.; Fu, Y.-X.: Dysregulated
LIGHT expression on T cells mediates intestinal inflammation and contributes
to IgA nephropathy. J. Clin. Invest. 113: 826-835, 2004.
9. Yu, P.; Lee, Y.; Liu, W.; Chin, R. K.; Wang, J.; Wang, Y.; Schietinger,
A.; Philip, M.; Schreiber, H.; Fu, Y.-X.: Priming of naive T cells
inside tumors leads to eradication of established tumors. Nature
Immun. 5: 141-149, 2004.
*FIELD* CN
Paul J. Converse - updated: 5/12/2011
Ada Hamosh - updated: 6/4/2007
Paul J. Converse - updated: 11/1/2006
Marla J. F. O'Neill - updated: 5/20/2004
Paul J. Converse - updated: 5/5/2004
Paul J. Converse - updated: 12/11/2001
Paul J. Converse - updated: 11/22/2000
*FIELD* CD
Paul J. Converse: 2/8/2000
*FIELD* ED
mgross: 05/13/2011
terry: 5/12/2011
carol: 8/14/2008
alopez: 6/18/2007
terry: 6/4/2007
mgross: 11/7/2006
terry: 11/1/2006
carol: 5/24/2004
terry: 5/20/2004
mgross: 5/5/2004
mgross: 2/22/2002
mgross: 1/9/2002
mgross: 1/8/2002
terry: 12/11/2001
mgross: 11/22/2000
carol: 11/1/2000
carol: 2/10/2000
carol: 2/9/2000