HHLA2_HUMAN
ID HHLA2_HUMAN Reviewed; 414 AA.
AC Q9UM44; B4DKN2; D3DN60; Q9NWQ6;
DT 19-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=HERV-H LTR-associating protein 2;
DE AltName: Full=Human endogenous retrovirus-H long terminal repeat-associating protein 2;
DE Flags: Precursor;
GN Name=HHLA2;
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 [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=10444326; DOI=10.1006/geno.1999.5877;
RA Mager D.L., Hunter D.G., Schertzer M., Freeman J.D.;
RT "Endogenous retroviruses provide the primary polyadenylation signal for two
RT new human genes (HHLA2 and HHLA3).";
RL Genomics 59:255-263(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Colon, and Ileal mucosa;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
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 [6]
RP FUNCTION IN T-CELL COSTIMULATION, INTERACTION WITH TMIGD2, TISSUE
RP SPECIFICITY, AND INDUCTION.
RX PubMed=23784006; DOI=10.1038/ncomms3043;
RA Zhu Y., Yao S., Iliopoulou B.P., Han X., Augustine M.M., Xu H.,
RA Phennicie R.T., Flies S.J., Broadwater M., Ruff W., Taube J.M., Zheng L.,
RA Luo L., Zhu G., Chen J., Chen L.;
RT "B7-H5 costimulates human T cells via CD28H.";
RL Nat. Commun. 4:2043-2043(2013).
CC -!- FUNCTION: Through interaction with TMIGD2, costimulates T-cells in the
CC context of TCR-mediated activation. Enhances T-cell proliferation and
CC cytokine production via an AKT-dependent signaling cascade.
CC {ECO:0000269|PubMed:23784006}.
CC -!- SUBUNIT: Interacts with TMIGD2. {ECO:0000269|PubMed:23784006}.
CC -!- INTERACTION:
CC Q9UM44; O43315: AQP9; NbExp=3; IntAct=EBI-2867874, EBI-17444777;
CC Q9UM44; Q6PL45-2: BRICD5; NbExp=3; IntAct=EBI-2867874, EBI-12244618;
CC Q9UM44; Q6UX41-6: BTNL8; NbExp=3; IntAct=EBI-2867874, EBI-17442596;
CC Q9UM44; Q7Z2K6: ERMP1; NbExp=3; IntAct=EBI-2867874, EBI-10976398;
CC Q9UM44; Q92520: FAM3C; NbExp=3; IntAct=EBI-2867874, EBI-2876774;
CC Q9UM44; Q0D2K0: NIPAL4; NbExp=3; IntAct=EBI-2867874, EBI-9550165;
CC Q9UM44; Q8IXM6: NRM; NbExp=3; IntAct=EBI-2867874, EBI-10262547;
CC Q9UM44; P0DJD7: PGA4; NbExp=3; IntAct=EBI-2867874, EBI-12957629;
CC Q9UM44; Q9NS64: RPRM; NbExp=3; IntAct=EBI-2867874, EBI-1052363;
CC Q9UM44; Q9NVC3: SLC38A7; NbExp=3; IntAct=EBI-2867874, EBI-10314552;
CC Q9UM44; Q96JW4: SLC41A2; NbExp=3; IntAct=EBI-2867874, EBI-10290130;
CC Q9UM44; Q9NRQ5: SMCO4; NbExp=3; IntAct=EBI-2867874, EBI-8640191;
CC Q9UM44; Q9NV12: TMEM140; NbExp=3; IntAct=EBI-2867874, EBI-2844246;
CC Q9UM44; Q9H2S6-2: TNMD; NbExp=3; IntAct=EBI-2867874, EBI-12003398;
CC Q9UM44; Q5BVD1: TTMP; NbExp=3; IntAct=EBI-2867874, EBI-10243654;
CC Q9UM44; Q9H1C4: UNC93B1; NbExp=3; IntAct=EBI-2867874, EBI-4401271;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9UM44-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UM44-2; Sequence=VSP_054729;
CC -!- TISSUE SPECIFICITY: Expressed at high levels in colon, kidney, testis,
CC lung and pancreas, and at lower levels in small intestine, liver and
CC skeletal muscle. In immune cells, highly expressed in B-cells,
CC dendritic cells and macrophages. Not detected in T-cells.
CC {ECO:0000269|PubMed:10444326, ECO:0000269|PubMed:23784006}.
CC -!- INDUCTION: Up-regulated in antigen-presenting cells in response to
CC inflammation. Induced in dendritic cells in response to IFNG, poly(I:C)
CC or heat-killed Listeria monocytogenes (at protein level).
CC {ECO:0000269|PubMed:23784006}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA91323.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF126162; AAD48396.1; -; mRNA.
DR EMBL; AK000692; BAA91323.1; ALT_SEQ; mRNA.
DR EMBL; AK296644; BAG59244.1; -; mRNA.
DR EMBL; AC078855; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135308; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79727.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79728.1; -; Genomic_DNA.
DR EMBL; BC035971; AAH35971.1; -; mRNA.
DR CCDS; CCDS46883.1; -. [Q9UM44-1]
DR CCDS; CCDS63713.1; -. [Q9UM44-2]
DR RefSeq; NP_001269485.1; NM_001282556.1. [Q9UM44-1]
DR RefSeq; NP_001269486.1; NM_001282557.1. [Q9UM44-1]
DR RefSeq; NP_001269487.1; NM_001282558.1.
DR RefSeq; NP_001269488.1; NM_001282559.1. [Q9UM44-2]
DR RefSeq; NP_009003.1; NM_007072.3. [Q9UM44-1]
DR RefSeq; XP_005247137.1; XM_005247080.3. [Q9UM44-1]
DR RefSeq; XP_016861131.1; XM_017005642.1.
DR AlphaFoldDB; Q9UM44; -.
DR SMR; Q9UM44; -.
DR BioGRID; 116320; 14.
DR IntAct; Q9UM44; 17.
DR STRING; 9606.ENSP00000350402; -.
DR GlyGen; Q9UM44; 4 sites, 1 O-linked glycan (1 site).
DR BioMuta; HHLA2; -.
DR DMDM; 74762781; -.
DR MassIVE; Q9UM44; -.
DR PaxDb; Q9UM44; -.
DR PeptideAtlas; Q9UM44; -.
DR PRIDE; Q9UM44; -.
DR ProteomicsDB; 4474; -.
DR ProteomicsDB; 85175; -. [Q9UM44-1]
DR ABCD; Q9UM44; 2 sequenced antibodies.
DR Antibodypedia; 32369; 209 antibodies from 28 providers.
DR DNASU; 11148; -.
DR Ensembl; ENST00000357759.9; ENSP00000350402.5; ENSG00000114455.14. [Q9UM44-1]
DR Ensembl; ENST00000467562.5; ENSP00000418345.1; ENSG00000114455.14. [Q9UM44-2]
DR Ensembl; ENST00000467761.6; ENSP00000419207.1; ENSG00000114455.14. [Q9UM44-1]
DR Ensembl; ENST00000489514.6; ENSP00000417856.2; ENSG00000114455.14. [Q9UM44-1]
DR Ensembl; ENST00000619531.4; ENSP00000482187.1; ENSG00000114455.14. [Q9UM44-1]
DR GeneID; 11148; -.
DR KEGG; hsa:11148; -.
DR MANE-Select; ENST00000467761.6; ENSP00000419207.1; NM_001282556.2; NP_001269485.1.
DR UCSC; uc003dwz.5; human. [Q9UM44-1]
DR CTD; 11148; -.
DR DisGeNET; 11148; -.
DR GeneCards; HHLA2; -.
DR HGNC; HGNC:4905; HHLA2.
DR HPA; ENSG00000114455; Tissue enriched (intestine).
DR MIM; 604371; gene.
DR neXtProt; NX_Q9UM44; -.
DR OpenTargets; ENSG00000114455; -.
DR PharmGKB; PA29278; -.
DR VEuPathDB; HostDB:ENSG00000114455; -.
DR eggNOG; ENOG502S3IN; Eukaryota.
DR GeneTree; ENSGT00940000162944; -.
DR InParanoid; Q9UM44; -.
DR OMA; PRFSWNK; -.
DR PhylomeDB; Q9UM44; -.
DR TreeFam; TF331083; -.
DR PathwayCommons; Q9UM44; -.
DR SignaLink; Q9UM44; -.
DR BioGRID-ORCS; 11148; 6 hits in 1063 CRISPR screens.
DR ChiTaRS; HHLA2; human.
DR GenomeRNAi; 11148; -.
DR Pharos; Q9UM44; Tbio.
DR PRO; PR:Q9UM44; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q9UM44; protein.
DR Bgee; ENSG00000114455; Expressed in rectum and 76 other tissues.
DR ExpressionAtlas; Q9UM44; baseline and differential.
DR Genevisible; Q9UM44; HS.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; IDA:UniProtKB.
DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:UniProtKB.
DR GO; GO:0001817; P:regulation of cytokine production; IBA:GO_Central.
DR GO; GO:0031295; P:T cell costimulation; IDA:UniProtKB.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IBA:GO_Central.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003597; Ig_C1-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR013106; Ig_V-set.
DR Pfam; PF07654; C1-set; 1.
DR Pfam; PF07686; V-set; 2.
DR SMART; SM00409; IG; 2.
DR SMART; SM00406; IGv; 2.
DR SUPFAM; SSF48726; SSF48726; 3.
DR PROSITE; PS50835; IG_LIKE; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW Membrane; Reference proteome; Repeat; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT CHAIN 23..414
FT /note="HERV-H LTR-associating protein 2"
FT /id="PRO_0000249709"
FT TRANSMEM 345..365
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 61..131
FT /note="Ig-like V-type 1"
FT DOMAIN 138..222
FT /note="Ig-like C1-type"
FT DOMAIN 235..328
FT /note="Ig-like V-type 2"
FT REGION 383..414
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 90
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 103
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 318
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 159..210
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 243..317
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 1..108
FT /note="MKAQTALSFFLILITSLSGSQGIFPLAFFIYVPMNEQIVIGRLDEDIILPSS
FT FERGSEVVIHWKYQDSYKVHSYYKGSDHLESQDPRYANRTSLFYNEIQNGNASLFF ->
FT MVMWNILKPRTHLLCMTNMFCTRHEGTDSTVFLPHSHNISEWIS (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054729"
FT VARIANT 30
FT /note="I -> T (in dbSNP:rs6779254)"
FT /id="VAR_027487"
FT VARIANT 344
FT /note="N -> K (in dbSNP:rs3792332)"
FT /id="VAR_027488"
FT VARIANT 364
FT /note="S -> R (in dbSNP:rs6779094)"
FT /id="VAR_027489"
SQ SEQUENCE 414 AA; 46850 MW; D645383E1562F70E CRC64;
MKAQTALSFF LILITSLSGS QGIFPLAFFI YVPMNEQIVI GRLDEDIILP SSFERGSEVV
IHWKYQDSYK VHSYYKGSDH LESQDPRYAN RTSLFYNEIQ NGNASLFFRR VSLLDEGIYT
CYVGTAIQVI TNKVVLKVGV FLTPVMKYEK RNTNSFLICS VLSVYPRPII TWKMDNTPIS
ENNMEETGSL DSFSINSPLN ITGSNSSYEC TIENSLLKQT WTGRWTMKDG LHKMQSEHVS
LSCQPVNDYF SPNQDFKVTW SRMKSGTFSV LAYYLSSSQN TIINESRFSW NKELINQSDF
SMNLMDLNLS DSGEYLCNIS SDEYTLLTIH TVHVEPSQET ASHNKGLWIL VPSAILAAFL
LIWSVKCCRA QLEARRSRHP ADGAQQERCC VPPGERCPSA PDNGEENVPL SGKV
