S39A8_HUMAN
ID S39A8_HUMAN Reviewed; 460 AA.
AC Q9C0K1; B4E2H3; Q96SM9; Q9BVC0; Q9NSA4;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Metal cation symporter ZIP8 {ECO:0000305|PubMed:12504855};
DE AltName: Full=BCG-induced integral membrane protein in monocyte clone 103 protein {ECO:0000303|PubMed:12504855};
DE AltName: Full=LIV-1 subfamily of ZIP zinc transporter 6;
DE Short=LZT-Hs6;
DE AltName: Full=Solute carrier family 39 member 8 {ECO:0000312|HGNC:HGNC:20862};
DE AltName: Full=Zrt- and Irt-like protein 8 {ECO:0000250|UniProtKB:Q91W10};
DE Short=ZIP-8 {ECO:0000250|UniProtKB:Q91W10};
DE Flags: Precursor;
GN Name=SLC39A8 {ECO:0000312|HGNC:HGNC:20862};
GN Synonyms=BIGM103 {ECO:0000303|PubMed:12504855},
GN ZIP8 {ECO:0000303|PubMed:18390834}; ORFNames=PP3105;
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), FUNCTION, TRANSPORTER ACTIVITY,
RP SUBCELLULAR LOCATION, INDUCTION, TISSUE SPECIFICITY, AND MOTIF.
RX PubMed=12504855; DOI=10.1006/geno.2002.7000;
RA Begum N.A., Kobayashi M., Moriwaki Y., Matsumoto M., Toyoshima K., Seya T.;
RT "Mycobacterium bovis BCG cell wall and lipopolysaccharide induce a novel
RT gene, BIGM103, encoding a 7-TM protein: identification of a new protein
RT family having Zn-transporter and Zn-metalloprotease signatures.";
RL Genomics 80:630-645(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Trachea;
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 MRNA] (ISOFORM 1).
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H., Qiu X.,
RA Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y., Shu H., Chen X.,
RA Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S., Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cervix, and Placenta;
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 [7]
RP FUNCTION, SUBCELLULAR LOCATION, INDUCTION, AND GLYCOSYLATION.
RX PubMed=18390834; DOI=10.1152/ajplung.00057.2008;
RA Besecker B., Bao S., Bohacova B., Papp A., Sadee W., Knoell D.L.;
RT "The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated
RT cytoprotection in lung epithelia.";
RL Am. J. Physiol. 294:L1127-L1136(2008).
RN [8]
RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19401385; DOI=10.1189/jlb.1208759;
RA Aydemir T.B., Liuzzi J.P., McClellan S., Cousins R.J.;
RT "Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in
RT activated human T cells.";
RL J. Leukoc. Biol. 86:337-348(2009).
RN [9]
RP FUNCTION, TRANSPORTER ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=22898811; DOI=10.1074/jbc.m112.367284;
RA Wang C.Y., Jenkitkasemwong S., Duarte S., Sparkman B.K., Shawki A.,
RA Mackenzie B., Knutson M.D.;
RT "ZIP8 is an iron and zinc transporter whose cell-surface expression is up-
RT regulated by cellular iron loading.";
RL J. Biol. Chem. 287:34032-34043(2012).
RN [10]
RP FUNCTION, AND INDUCTION.
RX PubMed=23403290; DOI=10.1016/j.celrep.2013.01.009;
RA Liu M.J., Bao S., Galvez-Peralta M., Pyle C.J., Rudawsky A.C.,
RA Pavlovicz R.E., Killilea D.W., Li C., Nebert D.W., Wewers M.D.,
RA Knoell D.L.;
RT "ZIP8 regulates host defense through zinc-mediated inhibition of NF-
RT kappaB.";
RL Cell Rep. 3:386-400(2013).
RN [11]
RP FUNCTION, AND TRANSPORTER ACTIVITY.
RX PubMed=27166256; DOI=10.18632/oncotarget.9205;
RA McDermott J.R., Geng X., Jiang L., Galvez-Peralta M., Chen F., Nebert D.W.,
RA Liu Z.;
RT "Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite
RT uptake.";
RL Oncotarget 7:35327-35340(2016).
RN [12]
RP FUNCTION, AND CHARACTERIZATION OF VARIANT THR-391.
RX PubMed=28481222; DOI=10.1172/jci90896;
RA Lin W., Vann D.R., Doulias P.T., Wang T., Landesberg G., Li X.,
RA Ricciotti E., Scalia R., He M., Hand N.J., Rader D.J.;
RT "Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and
RT manganese-dependent enzyme activity.";
RL J. Clin. Invest. 127:2407-2417(2017).
RN [13]
RP FUNCTION, TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=29337306; DOI=10.1172/jci96993;
RA Lin W., Li D., Cheng L., Li L., Liu F., Hand N.J., Epstein J.A.,
RA Rader D.J.;
RT "Zinc transporter Slc39a8 is essential for cardiac ventricular
RT compaction.";
RL J. Clin. Invest. 128:826-833(2018).
RN [14]
RP FUNCTION.
RX PubMed=29927450; DOI=10.1039/c8mt00079d;
RA Geng X., Liu L., Banes-Berceli A., Yang Z., Kang P., Shen J., Tsai K.J.,
RA Liu Z.;
RT "Role of ZIP8 in regulating cell morphology and NF-kappaB/Snail2
RT signaling.";
RL Metallomics 10:953-964(2018).
RN [15]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=28056086; DOI=10.1371/journal.pone.0169531;
RA Pyle C.J., Akhter S., Bao S., Dodd C.E., Schlesinger L.S., Knoell D.L.;
RT "Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through
RT ZIP8 Induction and C/EBPbeta Inhibition.";
RL PLoS ONE 12:E0169531-E0169531(2017).
RN [16]
RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=31699897; DOI=10.1074/jbc.ra119.009371;
RA Steimle B.L., Smith F.M., Kosman D.J.;
RT "The solute carriers ZIP8 and ZIP14 regulate manganese accumulation in
RT brain microvascular endothelial cells and control brain manganese levels.";
RL J. Biol. Chem. 294:19197-19208(2019).
RN [17]
RP VARIANT CDG2N ARG-38, FUNCTION, TRANSPORTER ACTIVITY, AND CHARACTERIZATION
RP OF VARIANT CDG2N ARG-38.
RX PubMed=26637978; DOI=10.1016/j.ajhg.2015.11.002;
RG Care4Rare Canada Consortium;
RA Boycott K.M., Beaulieu C.L., Kernohan K.D., Gebril O.H., Mhanni A.,
RA Chudley A.E., Redl D., Qin W., Hampson S., Kuery S., Tetreault M.,
RA Puffenberger E.G., Scott J.N., Bezieau S., Reis A., Uebe S., Schumacher J.,
RA Hegele R.A., McLeod D.R., Galvez-Peralta M., Majewski J., Ramaekers V.T.,
RA Nebert D.W., Innes A.M., Parboosingh J.S., Abou Jamra R.;
RT "Autosomal-recessive intellectual disability with cerebellar atrophy
RT syndrome caused by mutation of the manganese and zinc transporter gene
RT SLC39A8.";
RL Am. J. Hum. Genet. 97:886-893(2015).
RN [18]
RP VARIANTS CDG2N MET-33; ARG-38; CYS-204; THR-335 AND ASN-340.
RX PubMed=26637979; DOI=10.1016/j.ajhg.2015.11.003;
RA Park J.H., Hogrebe M., Grueneberg M., DuChesne I., von der Heiden A.L.,
RA Reunert J., Schlingmann K.P., Boycott K.M., Beaulieu C.L., Mhanni A.A.,
RA Innes A.M., Hoertnagel K., Biskup S., Gleixner E.M., Kurlemann G.,
RA Fiedler B., Omran H., Rutsch F., Wada Y., Tsiakas K., Santer R.,
RA Nebert D.W., Rust S., Marquardt T.;
RT "SLC39A8 deficiency: a disorder of manganese transport and glycosylation.";
RL Am. J. Hum. Genet. 97:894-903(2015).
RN [19]
RP FUNCTION, TRANSPORTER ACTIVITY, AND CHARACTERIZATION OF VARIANT THR-391.
RX PubMed=27466201; DOI=10.1093/hmg/ddw236;
RA Zhang R., Witkowska K., Afonso Guerra-Assuncao J., Ren M., Ng F.L.,
RA Mauro C., Tucker A.T., Caulfield M.J., Ye S.;
RT "A blood pressure-associated variant of the SLC39A8 gene influences
RT cellular cadmium accumulation and toxicity.";
RL Hum. Mol. Genet. 25:4117-4126(2016).
RN [20]
RP DISEASE, VARIANT SER-113, AND CHARACTERIZATION OF VARIANT SER-113.
RX PubMed=27995398; DOI=10.1007/s10545-016-0010-6;
RA Riley L.G., Cowley M.J., Gayevskiy V., Roscioli T., Thorburn D.R.,
RA Prelog K., Bahlo M., Sue C.M., Balasubramaniam S., Christodoulou J.;
RT "A SLC39A8 variant causes manganese deficiency, and glycosylation and
RT mitochondrial disorders.";
RL J. Inherit. Metab. Dis. 40:261-269(2017).
RN [21]
RP CHARACTERIZATION OF VARIANT CDG2N ARG-38, CHARACTERIZATION OF VARIANT
RP SER-113, FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP INDUCTION.
RX PubMed=29453449; DOI=10.1038/s41598-018-21464-0;
RA Choi E.K., Nguyen T.T., Gupta N., Iwase S., Seo Y.A.;
RT "Functional analysis of SLC39A8 mutations and their implications for
RT manganese deficiency and mitochondrial disorders.";
RL Sci. Rep. 8:3163-3163(2018).
CC -!- FUNCTION: Electroneutral transporter of the plasma membrane mediating
CC the cellular uptake of zinc and manganese, two divalent metal cations
CC important for development, tissue homeostasis or immunity
CC (PubMed:12504855, PubMed:22898811, PubMed:23403290, PubMed:29337306,
CC PubMed:26637978, PubMed:29453449). Functions as an energy-dependent
CC symporter, transporting through the membranes an electroneutral complex
CC composed of a divalent metal cation, a bicarbonate and a selenite anion
CC or yet a metal cation and two bicarbonate anions (PubMed:27166256,
CC PubMed:31699897). May also transport iron, mercury and cobalt through
CC membranes (PubMed:22898811). Beside these endogenous cellular
CC substrates, also imports cadmium a non-essential metal which is
CC cytotoxic and carcinogenic (PubMed:27466201). Through zinc import,
CC indirectly regulates the metal-dependent transcription factor MTF1 and
CC the expression of some metalloproteases involved in cartilage
CC catabolism and also probably heart development (PubMed:29337306). Also
CC indirectly regulates the expression of proteins involved in cell
CC morphology and cytoskeleton organization (PubMed:29927450). Indirectly
CC controls innate immune function and inflammatory response by regulating
CC zinc cellular uptake which in turn modulates the expression of genes
CC specific of these processes (PubMed:23403290, PubMed:28056086).
CC Protects, for instance, cells from injury and death at the onset of
CC inflammation (PubMed:18390834). By regulating zinc influx into
CC monocytes also directly modulates their adhesion to endothelial cells
CC and arteries (By similarity). At the apical membrane of hepatocytes,
CC reclaims manganese from the bile and regulates, through the systemic
CC levels of the nutrient, the activity of manganese-dependent enzymes
CC (PubMed:28481222). Also participates in manganese reabsorption in the
CC proximal tubule of the kidney (PubMed:26637978). By mediating the
CC extracellular uptake of manganese by cells of the blood-brain barrier,
CC may also play a role in the transport of the micronutrient to the brain
CC (PubMed:26637978, PubMed:31699897). Through manganese cellular uptake
CC also participates in mitochondrial proper function (PubMed:29453449).
CC Finally, also probably functions intracellularly, translocating zinc
CC from lysosome to cytosol to indirectly enhance the expression of
CC specific genes during TCR-mediated T cell activation (PubMed:19401385).
CC {ECO:0000250|UniProtKB:Q91W10, ECO:0000269|PubMed:12504855,
CC ECO:0000269|PubMed:18390834, ECO:0000269|PubMed:19401385,
CC ECO:0000269|PubMed:22898811, ECO:0000269|PubMed:23403290,
CC ECO:0000269|PubMed:26637978, ECO:0000269|PubMed:27166256,
CC ECO:0000269|PubMed:27466201, ECO:0000269|PubMed:28056086,
CC ECO:0000269|PubMed:28481222, ECO:0000269|PubMed:29337306,
CC ECO:0000269|PubMed:29453449, ECO:0000269|PubMed:29927450,
CC ECO:0000269|PubMed:31699897}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=hydrogencarbonate(out) + selenite(out) + Zn(2+)(out) =
CC hydrogencarbonate(in) + selenite(in) + Zn(2+)(in);
CC Xref=Rhea:RHEA:62264, ChEBI:CHEBI:17544, ChEBI:CHEBI:18212,
CC ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:27166256};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62265;
CC Evidence={ECO:0000269|PubMed:27166256};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 hydrogencarbonate(out) + Zn(2+)(out) = 2
CC hydrogencarbonate(in) + Zn(2+)(in); Xref=Rhea:RHEA:62252,
CC ChEBI:CHEBI:17544, ChEBI:CHEBI:29105;
CC Evidence={ECO:0000305|PubMed:12504855, ECO:0000305|PubMed:29337306};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62253;
CC Evidence={ECO:0000269|PubMed:29337306};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 hydrogencarbonate(out) + Mn(2+)(out) = 2
CC hydrogencarbonate(in) + Mn(2+)(in); Xref=Rhea:RHEA:62260,
CC ChEBI:CHEBI:17544, ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:31699897};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62261;
CC Evidence={ECO:0000269|PubMed:26637978, ECO:0000269|PubMed:29453449,
CC ECO:0000269|PubMed:31699897};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Cd(2+)(out) + 2 hydrogencarbonate(out) = Cd(2+)(in) + 2
CC hydrogencarbonate(in); Xref=Rhea:RHEA:62256, ChEBI:CHEBI:17544,
CC ChEBI:CHEBI:48775; Evidence={ECO:0000305|PubMed:27466201};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62257;
CC Evidence={ECO:0000269|PubMed:27466201};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Fe(2+)(in) = Fe(2+)(out); Xref=Rhea:RHEA:28486,
CC ChEBI:CHEBI:29033; Evidence={ECO:0000269|PubMed:22898811};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:28488;
CC Evidence={ECO:0000269|PubMed:22898811};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hg(2+)(in) = Hg(2+)(out); Xref=Rhea:RHEA:32815,
CC ChEBI:CHEBI:16793; Evidence={ECO:0000250|UniProtKB:Q91W10};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:32817;
CC Evidence={ECO:0000250|UniProtKB:Q91W10};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Co(2+)(in) = Co(2+)(out); Xref=Rhea:RHEA:28578,
CC ChEBI:CHEBI:48828; Evidence={ECO:0000250|UniProtKB:Q5FVQ0};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:28580;
CC Evidence={ECO:0000250|UniProtKB:Q5FVQ0};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.44 uM for Mn(2+) {ECO:0000269|PubMed:29453449};
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:Q5FVQ0}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12504855,
CC ECO:0000269|PubMed:18390834, ECO:0000269|PubMed:29337306,
CC ECO:0000269|PubMed:31699897}; Multi-pass membrane protein
CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:12504855,
CC ECO:0000269|PubMed:18390834, ECO:0000269|PubMed:19401385}; Multi-pass
CC membrane protein {ECO:0000255}. Apical cell membrane
CC {ECO:0000269|PubMed:31699897}; Multi-pass membrane protein
CC {ECO:0000255}. Basolateral cell membrane {ECO:0000269|PubMed:31699897};
CC Multi-pass membrane protein {ECO:0000255}. Note=Localizes to the
CC lysosome of activated T-cells (PubMed:19401385). A large fraction of
CC the protein is found intracellularly in microvascular capillary
CC endothelial cells that constitute the blood-brain barrier
CC (PubMed:31699897). Localized and functional at both apical and
CC basolateral membranes of microvascular capillary endothelial cells that
CC constitute the blood-brain barrier (PubMed:31699897).
CC {ECO:0000269|PubMed:19401385, ECO:0000269|PubMed:31699897}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9C0K1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9C0K1-2; Sequence=VSP_029884, VSP_029885;
CC Name=3;
CC IsoId=Q9C0K1-3; Sequence=VSP_043675;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed (PubMed:12504855,
CC PubMed:22898811, PubMed:28056086, PubMed:31699897). Expressed in
CC thymus, placenta, lung, liver, pancreas, salivary gland and, to a lower
CC extent, in spleen, testis, ovary, small intestine, colon, leukocyte,
CC heart. Highest expression is observed in pancreas (PubMed:12504855).
CC Expressed by macrophages (at protein level) (PubMed:28056086).
CC Expressed by microvascular capillary endothelial cells that constitute
CC the blood-brain barrier (at protein level) (PubMed:31699897).
CC {ECO:0000269|PubMed:12504855, ECO:0000269|PubMed:22898811,
CC ECO:0000269|PubMed:28056086, ECO:0000269|PubMed:31699897}.
CC -!- INDUCTION: Up-regulated by manganese (PubMed:29453449). Up-regulated by
CC lipopolysaccharides (at protein level) (PubMed:23403290,
CC PubMed:28056086). Up-regulated by inflammatory cytokines like TNF
CC (PubMed:12504855, PubMed:18390834). Down-regulated following phorbol
CC ester treatment (PubMed:12504855). Up-regulated by zinc and T-cell
CC activation (PubMed:19401385). {ECO:0000269|PubMed:12504855,
CC ECO:0000269|PubMed:18390834, ECO:0000269|PubMed:19401385,
CC ECO:0000269|PubMed:23403290, ECO:0000269|PubMed:28056086,
CC ECO:0000269|PubMed:29453449}.
CC -!- INDUCTION: (Microbial infection) Up-regulated by live and heat-killed
CC Mycobacterium bovis bacterial cell wall. {ECO:0000269|PubMed:12504855}.
CC -!- PTM: N-glycosylated (PubMed:18390834). N-glycosylation is not required
CC for proper iron and zinc transport (By similarity).
CC {ECO:0000250|UniProtKB:Q5FVQ0, ECO:0000269|PubMed:18390834}.
CC -!- DISEASE: Congenital disorder of glycosylation 2N (CDG2N) [MIM:616721]:
CC A form of congenital disorder of glycosylation, a genetically
CC heterogeneous group of autosomal recessive, multisystem disorders
CC caused by a defect in glycoprotein biosynthesis and characterized by
CC under-glycosylated serum glycoproteins. Congenital disorders of
CC glycosylation result in a wide variety of clinical features, such as
CC defects in the nervous system development, psychomotor retardation,
CC dysmorphic features, hypotonia, coagulation disorders, and
CC immunodeficiency. The broad spectrum of features reflects the critical
CC role of N-glycoproteins during embryonic development, differentiation,
CC and maintenance of cell functions. {ECO:0000269|PubMed:26637978,
CC ECO:0000269|PubMed:26637979, ECO:0000269|PubMed:29453449}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Note=Rare variants in SLC39A8 may be a cause of Leigh-like
CC mitochondrial syndrome characterized by profound developmental delay,
CC dystonia, seizures and failure to thrive.
CC {ECO:0000269|PubMed:27995398}.
CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; AB020970; BAA96442.1; -; mRNA.
DR EMBL; AB040120; BAB21559.1; -; mRNA.
DR EMBL; AK027652; BAB55268.1; -; mRNA.
DR EMBL; AK304274; BAG65135.1; -; mRNA.
DR EMBL; AF193052; AAG22480.1; -; mRNA.
DR EMBL; AC098487; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP002023; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471057; EAX06130.1; -; Genomic_DNA.
DR EMBL; BC001320; AAH01320.1; -; mRNA.
DR EMBL; BC012125; AAH12125.1; -; mRNA.
DR CCDS; CCDS3656.1; -. [Q9C0K1-1]
DR CCDS; CCDS47117.1; -. [Q9C0K1-3]
DR RefSeq; NP_001128618.1; NM_001135146.1. [Q9C0K1-1]
DR RefSeq; NP_001128619.1; NM_001135147.1. [Q9C0K1-3]
DR RefSeq; NP_001128620.1; NM_001135148.1. [Q9C0K1-2]
DR RefSeq; NP_071437.3; NM_022154.5. [Q9C0K1-1]
DR RefSeq; XP_005263234.1; XM_005263177.1. [Q9C0K1-1]
DR RefSeq; XP_016864029.1; XM_017008540.1.
DR RefSeq; XP_016864030.1; XM_017008541.1. [Q9C0K1-2]
DR AlphaFoldDB; Q9C0K1; -.
DR SMR; Q9C0K1; -.
DR BioGRID; 122072; 35.
DR IntAct; Q9C0K1; 27.
DR MINT; Q9C0K1; -.
DR STRING; 9606.ENSP00000378310; -.
DR DrugBank; DB14533; Zinc chloride.
DR DrugBank; DB14548; Zinc sulfate, unspecified form.
DR TCDB; 2.A.5.4.15; the zinc (zn(2+))-iron (fe(2+)) permease (zip) family.
DR GlyGen; Q9C0K1; 3 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q9C0K1; -.
DR PhosphoSitePlus; Q9C0K1; -.
DR BioMuta; SLC39A8; -.
DR DMDM; 74733496; -.
DR EPD; Q9C0K1; -.
DR jPOST; Q9C0K1; -.
DR MassIVE; Q9C0K1; -.
DR MaxQB; Q9C0K1; -.
DR PaxDb; Q9C0K1; -.
DR PeptideAtlas; Q9C0K1; -.
DR PRIDE; Q9C0K1; -.
DR ProteomicsDB; 80068; -. [Q9C0K1-1]
DR ProteomicsDB; 80069; -. [Q9C0K1-2]
DR ProteomicsDB; 80070; -. [Q9C0K1-3]
DR Antibodypedia; 45037; 177 antibodies from 29 providers.
DR DNASU; 64116; -.
DR Ensembl; ENST00000356736.5; ENSP00000349174.4; ENSG00000138821.14. [Q9C0K1-1]
DR Ensembl; ENST00000394833.6; ENSP00000378310.2; ENSG00000138821.14. [Q9C0K1-1]
DR Ensembl; ENST00000682227.1; ENSP00000508363.1; ENSG00000138821.14. [Q9C0K1-1]
DR Ensembl; ENST00000682932.1; ENSP00000507414.1; ENSG00000138821.14. [Q9C0K1-1]
DR Ensembl; ENST00000683412.1; ENSP00000507538.1; ENSG00000138821.14. [Q9C0K1-1]
DR GeneID; 64116; -.
DR KEGG; hsa:64116; -.
DR MANE-Select; ENST00000356736.5; ENSP00000349174.4; NM_001135146.2; NP_001128618.1.
DR UCSC; uc003hwb.2; human. [Q9C0K1-1]
DR CTD; 64116; -.
DR DisGeNET; 64116; -.
DR GeneCards; SLC39A8; -.
DR HGNC; HGNC:20862; SLC39A8.
DR HPA; ENSG00000138821; Tissue enhanced (lung).
DR MalaCards; SLC39A8; -.
DR MIM; 608732; gene.
DR MIM; 616721; phenotype.
DR neXtProt; NX_Q9C0K1; -.
DR OpenTargets; ENSG00000138821; -.
DR Orphanet; 468699; SLC39A8-CDG.
DR PharmGKB; PA134931507; -.
DR VEuPathDB; HostDB:ENSG00000138821; -.
DR eggNOG; KOG2693; Eukaryota.
DR GeneTree; ENSGT00940000158926; -.
DR HOGENOM; CLU_015114_13_0_1; -.
DR InParanoid; Q9C0K1; -.
DR OMA; WLRGQRI; -.
DR OrthoDB; 657777at2759; -.
DR PhylomeDB; Q9C0K1; -.
DR TreeFam; TF318470; -.
DR PathwayCommons; Q9C0K1; -.
DR Reactome; R-HSA-442380; Zinc influx into cells by the SLC39 gene family.
DR SignaLink; Q9C0K1; -.
DR BioGRID-ORCS; 64116; 13 hits in 1079 CRISPR screens.
DR ChiTaRS; SLC39A8; human.
DR GenomeRNAi; 64116; -.
DR Pharos; Q9C0K1; Tbio.
DR PRO; PR:Q9C0K1; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9C0K1; protein.
DR Bgee; ENSG00000138821; Expressed in parotid gland and 193 other tissues.
DR ExpressionAtlas; Q9C0K1; baseline and differential.
DR Genevisible; Q9C0K1; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0031090; C:organelle membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0015296; F:anion:cation symporter activity; ISS:UniProtKB.
DR GO; GO:0015106; F:bicarbonate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; IMP:UniProtKB.
DR GO; GO:0015087; F:cobalt ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IMP:UniProtKB.
DR GO; GO:0097079; F:selenite:proton symporter activity; IDA:UniProtKB.
DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0140412; F:zinc:bicarbonate symporter activity; IEA:Ensembl.
DR GO; GO:0006525; P:arginine metabolic process; ISS:UniProtKB.
DR GO; GO:0015701; P:bicarbonate transport; ISS:UniProtKB.
DR GO; GO:0070574; P:cadmium ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:1990079; P:cartilage homeostasis; ISS:UniProtKB.
DR GO; GO:0006876; P:cellular cadmium ion homeostasis; IMP:UniProtKB.
DR GO; GO:0030026; P:cellular manganese ion homeostasis; ISS:UniProtKB.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; IDA:UniProtKB.
DR GO; GO:0006824; P:cobalt ion transport; ISS:UniProtKB.
DR GO; GO:0030198; P:extracellular matrix organization; IMP:UniProtKB.
DR GO; GO:0098711; P:iron ion import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0061757; P:leukocyte adhesion to arterial endothelial cell; ISS:UniProtKB.
DR GO; GO:0071421; P:manganese ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:1990540; P:mitochondrial manganese ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0097080; P:plasma membrane selenite transport; IDA:UniProtKB.
DR GO; GO:0006487; P:protein N-linked glycosylation; ISS:UniProtKB.
DR GO; GO:0042391; P:regulation of membrane potential; IMP:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0006351; P:transcription, DNA-templated; IEA:Ensembl.
DR GO; GO:0071578; P:zinc ion import across plasma membrane; IMP:UniProtKB.
DR GO; GO:0071577; P:zinc ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006829; P:zinc ion transport; IMP:UniProtKB.
DR InterPro; IPR003689; ZIP.
DR Pfam; PF02535; Zip; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Congenital disorder of glycosylation;
KW Glycoprotein; Ion transport; Lysosome; Membrane; Reference proteome;
KW Signal; Transmembrane; Transmembrane helix; Transport; Zinc;
KW Zinc transport.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT CHAIN 23..460
FT /note="Metal cation symporter ZIP8"
FT /evidence="ECO:0000255"
FT /id="PRO_0000312707"
FT TOPO_DOM 23..132
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q5FVQ0"
FT TRANSMEM 133..153
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 154..160
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q5FVQ0"
FT TRANSMEM 161..181
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 182..191
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q5FVQ0"
FT TRANSMEM 192..212
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 213..365
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q5FVQ0"
FT TRANSMEM 366..386
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 387..388
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q5FVQ0"
FT TRANSMEM 389..409
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 410..429
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q5FVQ0"
FT TRANSMEM 430..450
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 451..460
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q5FVQ0"
FT MOTIF 343..348
FT /note="XEXPHE-motif"
FT /evidence="ECO:0000305|PubMed:12504855"
FT CARBOHYD 40
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 88
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..67
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_029884"
FT VAR_SEQ 68..72
FT /note="QLHFN -> MHQHA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_029885"
FT VAR_SEQ 423..460
FT /note="VTGRKTDFTFFMIQNAGMLTGFTAILLITLYAGEIELE -> IIKWATDDIK
FT SQLHLLWIYTAR (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043675"
FT VARIANT 33
FT /note="V -> M (in CDG2N; dbSNP:rs373562040)"
FT /evidence="ECO:0000269|PubMed:26637979"
FT /id="VAR_076241"
FT VARIANT 38
FT /note="G -> R (in CDG2N; loss of manganese ion
FT transmembrane transport; loss of localization to the plasma
FT membrane; retained in the endoplasmic reticulum; no effect
FT on protein abundance; dbSNP:rs778210210)"
FT /evidence="ECO:0000269|PubMed:26637978,
FT ECO:0000269|PubMed:26637979, ECO:0000269|PubMed:29453449"
FT /id="VAR_076242"
FT VARIANT 113
FT /note="C -> S (probable disease-associated variant found in
FT patients with Leigh-like syndrome; no effect on protein
FT abundance; loss of localization to the plasma membrane;
FT retained in the endoplasmic reticulum; loss of manganese
FT ion transmembrane transport; dbSNP:rs1444255127)"
FT /evidence="ECO:0000269|PubMed:27995398"
FT /id="VAR_083148"
FT VARIANT 204
FT /note="G -> C (in CDG2N; dbSNP:rs779241085)"
FT /evidence="ECO:0000269|PubMed:26637979"
FT /id="VAR_076243"
FT VARIANT 335
FT /note="S -> T (in CDG2N; dbSNP:rs864309660)"
FT /evidence="ECO:0000269|PubMed:26637979"
FT /id="VAR_076244"
FT VARIANT 340
FT /note="I -> N (in CDG2N; no detectable serum or urinary
FT manganese levels in an affected individual who also carries
FT R-38 mutation; dbSNP:rs864309659)"
FT /evidence="ECO:0000269|PubMed:26637979"
FT /id="VAR_076245"
FT VARIANT 391
FT /note="A -> T (no effect on protein abundance; decreased
FT cadmium ion transmembrane transport; increased resistance
FT to cadmium cytotoxicity; associated with decreased activity
FT of manganese-dependent enzymes; dbSNP:rs13107325)"
FT /evidence="ECO:0000269|PubMed:27466201,
FT ECO:0000269|PubMed:28481222"
FT /id="VAR_037551"
FT CONFLICT 241
FT /note="K -> E (in Ref. 3; BAB55268)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 460 AA; 49631 MW; E5C03F4576E11E2F CRC64;
MAPGRAVAGL LLLAAAGLGG VAEGPGLAFS EDVLSVFGAN LSLSAAQLQH LLEQMGAASR
VGVPEPGQLH FNQCLTAEEI FSLHGFSNAT QITSSKFSVI CPAVLQQLNF HPCEDRPKHK
TRPSHSEVWG YGFLSVTIIN LASLLGLILT PLIKKSYFPK ILTFFVGLAI GTLFSNAIFQ
LIPEAFGFDP KVDSYVEKAV AVFGGFYLLF FFERMLKMLL KTYGQNGHTH FGNDNFGPQE
KTHQPKALPA INGVTCYANP AVTEANGHIH FDNVSVVSLQ DGKKEPSSCT CLKGPKLSEI
GTIAWMITLC DALHNFIDGL AIGASCTLSL LQGLSTSIAI LCEEFPHELG DFVILLNAGM
STRQALLFNF LSACSCYVGL AFGILVGNNF APNIIFALAG GMFLYISLAD MFPEMNDMLR
EKVTGRKTDF TFFMIQNAGM LTGFTAILLI TLYAGEIELE
