ID LYSET_HUMAN Reviewed; 163 AA. AC Q8N6I4; J3KQ65; Q9Y4S5; DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot. DT 20-JAN-2009, sequence version 4. DT 24-JAN-2024, entry version 140. DE RecName: Full=Lysosomal enzyme trafficking factor {ECO:0000303|PubMed:36074821}; DE AltName: Full=GNPTAB cleavage and activity factor {ECO:0000303|PubMed:36096887}; DE Short=GCAF {ECO:0000303|PubMed:36096887}; DE AltName: Full=Transmembrane protein 251; GN Name=LYSET {ECO:0000312|HGNC:HGNC:20218}; Synonyms=C14orf109, TMEM251; 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 [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Embryonic brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), AND NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 1-149 (ISOFORM 1). RC TISSUE=Brain, and Melanoma; 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 [5] RP SUBCELLULAR LOCATION, INVOLVEMENT IN DMAN, AND VARIANTS DMAN TRP-39 AND RP 66-TYR--THR-163 DEL. RX PubMed=33252156; DOI=10.1002/humu.24139; RA Ain N.U., Muhammad N., Dianatpour M., Baroncelli M., Iqbal M., Fard M.A.F., RA Bukhari I., Ahmed S., Hajipour M., Tabatabaie Z., Foroutan H., Nilsson O., RA Faghihi M.A., Makitie O., Naz S.; RT "Biallelic TMEM251 variants in patients with severe skeletal dysplasia and RT extreme short stature."; RL Hum. Mutat. 42:89-101(2021). RN [6] RP FUNCTION, INTERACTION WITH GNPTAB, AND CHARACTERIZATION OF VARIANTS DMAN RP TRP-39 AND 66-TYR--THR-163 DEL. RX PubMed=36074822; DOI=10.1126/science.abn5637; RA Pechincha C., Groessl S., Kalis R., de Almeida M., Zanotti A., Wittmann M., RA Schneider M., de Campos R.P., Rieser S., Brandstetter M., Schleiffer A., RA Mueller-Decker K., Helm D., Jabs S., Haselbach D., Lemberg M.K., Zuber J., RA Palm W.; RT "Lysosomal enzyme trafficking factor LYSET enables nutritional usage of RT extracellular proteins."; RL Science 2022:eabn5637-eabn5637(2022). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH GNPTAB, CHARACTERIZATION RP OF VARIANT DMAN TRP-39, MUTAGENESIS OF THR-86; ILE-136 AND LYS-150, AND RP FUNCTION (MICROBIAL INFECTION). RX PubMed=36074821; DOI=10.1126/science.abn5648; RA Richards C.M., Jabs S., Qiao W., Varanese L.D., Schweizer M., Mosen P.R., RA Riley N.M., Kluessendorf M., Zengel J.R., Flynn R.A., Rustagi A., RA Widen J.C., Peters C.E., Ooi Y.S., Xie X., Shi P.Y., Bartenschlager R., RA Puschnik A.S., Bogyo M., Bertozzi C.R., Blish C.A., Winter D., RA Nagamine C.M., Braulke T., Carette J.E.; RT "The human disease gene LYSET is essential for lysosomal enzyme transport RT and viral infection."; RL Science 2022:eabn5648-eabn5648(2022). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH GNPTAB AND MBTPS1. RX PubMed=36096887; DOI=10.1038/s41467-022-33025-1; RA Zhang W., Yang X., Li Y., Yu L., Zhang B., Zhang J., Cho W.J., RA Venkatarangan V., Chen L., Burugula B.B., Bui S., Wang Y., Duan C., RA Kitzman J.O., Li M.; RT "GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6- RT phosphate pathway."; RL Nat. Commun. 13:5351-5351(2022). CC -!- FUNCTION: Required for mannose-6-phosphate-dependent trafficking of CC lysosomal enzymes (PubMed:36074822, PubMed:36096887, PubMed:36074821). CC LYSET bridges GlcNAc-1-phosphate transferase (GNPTAB), to the membrane- CC bound transcription factor site-1 protease (MBTPS1), thus allowing CC proteolytic activation of the GNPTAB. GNPTAB is involved in the CC regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal CC enzymes (PubMed:36096887, PubMed:36074822, PubMed:36074821). LYSET is CC thus an essential factor for maturation and delivery of lysosomal CC hydrolases (PubMed:36074822). {ECO:0000269|PubMed:36074821, CC ECO:0000269|PubMed:36074822, ECO:0000269|PubMed:36096887}. CC -!- FUNCTION: (Microbial infection) Essential for infection by muliple CC viruses, including SARS-CoV-2, that utilize activated cathepsins for CC entry after M6P-dependent lysosomal transport. CC {ECO:0000269|PubMed:36074821}. CC -!- SUBUNIT: Interacts with GNPTAB; this interaction is important for CC proper localization of GNPTAB in Golgi stacks (PubMed:36074821, CC PubMed:36096887). Interacts with MBTPS1 (PubMed:36096887). CC {ECO:0000269|PubMed:36074821, ECO:0000269|PubMed:36096887}. CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane CC {ECO:0000269|PubMed:33252156, ECO:0000269|PubMed:36074821, CC ECO:0000269|PubMed:36096887}; Multi-pass membrane protein CC {ECO:0000255}. Note=Colocalizes with GNPTAB and GNPTG in Golgi CC apparatus cisternae. {ECO:0000269|PubMed:36074821}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8N6I4-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8N6I4-2; Sequence=VSP_036175; CC Name=3; CC IsoId=Q8N6I4-3; Sequence=VSP_045689; CC -!- DISEASE: Dysostosis multiplex, Ain-Naz type (DMAN) [MIM:619345]: An CC autosomal recessive, severe skeletal disease characterized by features CC of dysostosis multiplex, severe short stature, coarse facies with broad CC nose and prominent lips, protruding abdomens, and progressive skeletal CC changes causing gradual mobility loss. Death in childhood or early CC adulthood may occur. {ECO:0000269|PubMed:33252156, CC ECO:0000269|PubMed:36074821, ECO:0000269|PubMed:36074822}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the LYSET family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH30119.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL080118; CAB45717.2; -; mRNA. DR EMBL; AL110118; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471061; EAW81518.1; -; Genomic_DNA. DR EMBL; BC030119; AAH30119.2; ALT_INIT; mRNA. DR EMBL; BM554490; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; CX785861; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS41980.1; -. [Q8N6I4-2] DR CCDS; CCDS45158.2; -. [Q8N6I4-1] DR PIR; T12454; T12454. DR RefSeq; NP_001092091.1; NM_001098621.1. [Q8N6I4-1] DR RefSeq; NP_056491.1; NM_015676.1. [Q8N6I4-2] DR AlphaFoldDB; Q8N6I4; -. DR BioGRID; 117597; 3. DR STRING; 9606.ENSP00000388431; -. DR TCDB; 8.A.208.1.1; the lysosomal enzyme trafficking factor (lyset) family. DR SwissPalm; Q8N6I4; -. DR BioMuta; TMEM251; -. DR DMDM; 221222535; -. DR MassIVE; Q8N6I4; -. DR MaxQB; Q8N6I4; -. DR PaxDb; 9606-ENSP00000388431; -. DR PeptideAtlas; Q8N6I4; -. DR ProteomicsDB; 72180; -. [Q8N6I4-1] DR ProteomicsDB; 72181; -. [Q8N6I4-2] DR Antibodypedia; 64066; 5 antibodies from 5 providers. DR DNASU; 26175; -. DR Ensembl; ENST00000283534.4; ENSP00000283534.4; ENSG00000153485.6. [Q8N6I4-2] DR Ensembl; ENST00000415050.3; ENSP00000388431.3; ENSG00000153485.6. [Q8N6I4-1] DR Ensembl; ENST00000622205.2; ENSP00000478917.1; ENSG00000275947.2. [Q8N6I4-3] DR Ensembl; ENST00000626767.1; ENSP00000486678.1; ENSG00000275947.2. [Q8N6I4-2] DR GeneID; 26175; -. DR KEGG; hsa:26175; -. DR MANE-Select; ENST00000415050.3; ENSP00000388431.3; NM_001098621.4; NP_001092091.2. DR UCSC; uc001ybk.4; human. [Q8N6I4-1] DR AGR; HGNC:20218; -. DR CTD; 26175; -. DR GeneCards; LYSET; -. DR HGNC; HGNC:20218; LYSET. DR HPA; ENSG00000153485; Low tissue specificity. DR MalaCards; LYSET; -. DR MIM; 619332; gene. DR MIM; 619345; phenotype. DR neXtProt; NX_Q8N6I4; -. DR OpenTargets; ENSG00000153485; -. DR PharmGKB; PA134977710; -. DR VEuPathDB; HostDB:ENSG00000153485; -. DR eggNOG; ENOG502RY2J; Eukaryota. DR GeneTree; ENSGT00390000007473; -. DR HOGENOM; CLU_133007_0_0_1; -. DR InParanoid; Q8N6I4; -. DR OMA; AYYIFEV; -. DR OrthoDB; 5383730at2759; -. DR PhylomeDB; Q8N6I4; -. DR TreeFam; TF332722; -. DR PathwayCommons; Q8N6I4; -. DR BioGRID-ORCS; 26175; 29 hits in 1166 CRISPR screens. DR GenomeRNAi; 26175; -. DR Pharos; Q8N6I4; Tdark. DR PRO; PR:Q8N6I4; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q8N6I4; Protein. DR Bgee; ENSG00000153485; Expressed in islet of Langerhans and 101 other cell types or tissues. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0031985; C:Golgi cisterna; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0007041; P:lysosomal transport; IMP:UniProtKB. DR GO; GO:0007040; P:lysosome organization; IMP:UniProtKB. DR GO; GO:0060627; P:regulation of vesicle-mediated transport; IMP:UniProtKB. DR InterPro; IPR028024; LYSET. DR PANTHER; PTHR31925; TRANSMEMBRANE PROTEIN 251; 1. DR PANTHER; PTHR31925:SF1; TRANSMEMBRANE PROTEIN 251; 1. DR Pfam; PF15190; TMEM251; 1. DR Genevisible; Q8N6I4; HS. PE 1: Evidence at protein level; KW Alternative splicing; Disease variant; Dwarfism; Golgi apparatus; KW Host-virus interaction; Membrane; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..163 FT /note="Lysosomal enzyme trafficking factor" FT /id="PRO_0000089916" FT TRANSMEM 40..60 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 98..118 FT /note="Helical" FT /evidence="ECO:0000255" FT VAR_SEQ 1..32 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:17974005" FT /id="VSP_036175" FT VAR_SEQ 1 FT /note="M -> MLAFSEM (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_045689" FT VARIANT 39 FT /note="R -> W (in DMAN; lower protein expression. Fails to FT rescue the lysosomal trafficking defect in LYSET-deficient FT cells. Severe reduction of interaction with GNPTAB)" FT /evidence="ECO:0000269|PubMed:33252156, FT ECO:0000269|PubMed:36074821, ECO:0000269|PubMed:36074822" FT /id="VAR_085583" FT VARIANT 66..163 FT /note="Missing (in DMAN; no protein expression. Fails to FT rescue the lysosomal trafficking defect in LYSET-deficient FT cells)" FT /evidence="ECO:0000269|PubMed:33252156" FT /id="VAR_087348" FT MUTAGEN 86 FT /note="T->I: Rescues the lysosomal trafficking defect in FT LYSET-deficient cells." FT /evidence="ECO:0000269|PubMed:36074821" FT MUTAGEN 136 FT /note="I->V: Rescues the lysosomal trafficking defect in FT LYSET-deficient cells." FT /evidence="ECO:0000269|PubMed:36074821" FT MUTAGEN 150 FT /note="K->N: Rescues the lysosomal trafficking defect in FT LYSET-deficient cells." FT /evidence="ECO:0000269|PubMed:36074821" FT CONFLICT 152..153 FT /note="SN -> FY (in Ref. 4; BM554490)" FT /evidence="ECO:0000305" SQ SEQUENCE 163 AA; 18747 MW; 805D11CD73B20650 CRC64; MPKPPDYSEL SDSLTLAVGT GRFSGPLHRA WRMMNFRQRM GWIGVGLYLL ASAAAFYYVF EISETYNRLA LEHIQQHPEE PLEGTTWTHS LKAQLLSLPF WVWTVIFLVP YLQMFLFLYS CTRADPKTVG YCIIPICLAV ICNRHQAFVK ASNQISRLQL IDT //