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Identification
HMDB Protein ID HMDBP13948
Secondary Accession Numbers None
Name Solute carrier family 15 member 4
Synonyms
  1. Peptide transporter 4
  2. Peptide/histidine transporter 1
  3. hPHT1
Gene Name SLC15A4
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune response (PubMed:16289537, PubMed:25238095, PubMed:29224352). Able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans (PubMed:29224352, PubMed:31073693). Transporter activity is pH-dependent and maximized in the acidic lysosomal environment (By similarity). Involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycans across the endolysosomal membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand (PubMed:25238095, PubMed:29224352). Required for TLR7, TLR8 and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) (PubMed:25238095). Independently of its transporter activity, also promotes the recruitment of innate immune adapter TASL to endolysosome downstream of TLR7, TLR8 and TLR9: TASL recruitment leads to the specific recruitment and activation of IRF5 (PubMed:32433612). Required for isotype class switch recombination to IgG2c isotype in response to TLR9 stimulation (By similarity). Required for mast cell secretory-granule homeostasis by limiting mast cell functions and inflammatory responses (By similarity).
Pathways Not Available
Reactions Not Available
GO Classification
Biological Process
dipeptide import across plasma membrane
histidine transport
L-histidine transmembrane export from vacuole
positive regulation of innate immune response
mast cell homeostasis
peptidoglycan transport
positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
positive regulation of toll-like receptor 7 signaling pathway
positive regulation of toll-like receptor 8 signaling pathway
regulation of isotype switching to IgG isotypes
regulation of nucleotide-binding oligomerization domain containing signaling pathway
ion transport
neutrophil degranulation
protein transport
positive regulation of toll-like receptor 9 signaling pathway
innate immune response
Cellular Component
endolysosome membrane
integral component of endosome membrane
integral component of lysosomal membrane
specific granule membrane
plasma membrane
early endosome membrane
lysosomal membrane
Molecular Function
dipeptide transmembrane transporter activity
L-histidine transmembrane transporter activity
peptide:proton symporter activity
peptidoglycan transmembrane transporter activity
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 577
Molecular Weight 62032.8
Theoretical pI 8.996
Pfam Domain Function
Signals Not Available
Transmembrane Regions
  • 49-69;76-96;105-125;158-178;194-214;222-242;318-338;363-383;405-425;459-479;490-510;535-555;
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q8N697
UniProtKB/Swiss-Prot Entry Name S15A4_HUMAN
PDB IDs Not Available
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [PubMed:14702039 ]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  3. Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L, Zhou X, Li H, Qiu X, Zhong F, He L, Yu J, Yao G, Jiang H, Qian L, Yu Y, Shu H, Chen X, Xu H, Guo M, Pan Z, Chen Y, Ge C, Yang S, Gu J: Large-scale cDNA transfection screening for genes related to cancer development and progression. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15724-9. Epub 2004 Oct 21. [PubMed:15498874 ]
  4. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S: Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013 Jan 4;12(1):260-71. doi: 10.1021/pr300630k. Epub 2012 Dec 18. [PubMed:23186163 ]
  5. Herrera-Ruiz D, Wang Q, Gudmundsson OS, Cook TJ, Smith RL, Faria TN, Knipp GT: Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 in vitro cell culture model, and multiple human tissues. AAPS PharmSci. 2001;3(1):E9. doi: 10.1208/ps030109. [PubMed:11741260 ]
  6. Botka CW, Wittig TW, Graul RC, Nielsen CU, Higaka K, Amidon GL, Sadee W: Human proton/oligopeptide transporter (POT) genes: identification of putative human genes using bioinformatics. AAPS PharmSci. 2000;2(2):E16. doi: 10.1208/ps020216. [PubMed:11741232 ]
  7. Bhardwaj RK, Herrera-Ruiz D, Eltoukhy N, Saad M, Knipp GT: The functional evaluation of human peptide/histidine transporter 1 (hPHT1) in transiently transfected COS-7 cells. Eur J Pharm Sci. 2006 Apr;27(5):533-42. doi: 10.1016/j.ejps.2005.09.014. Epub 2005 Nov 10. [PubMed:16289537 ]
  8. Kobayashi T, Shimabukuro-Demoto S, Yoshida-Sugitani R, Furuyama-Tanaka K, Karyu H, Sugiura Y, Shimizu Y, Hosaka T, Goto M, Kato N, Okamura T, Suematsu M, Yokoyama S, Toyama-Sorimachi N: The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity. 2014 Sep 18;41(3):375-388. doi: 10.1016/j.immuni.2014.08.011. [PubMed:25238095 ]
  9. Song F, Hu Y, Wang Y, Smith DE, Jiang H: Functional Characterization of Human Peptide/Histidine Transporter 1 in Stably Transfected MDCK Cells. Mol Pharm. 2018 Feb 5;15(2):385-393. doi: 10.1021/acs.molpharmaceut.7b00728. Epub 2018 Jan 2. [PubMed:29224352 ]
  10. Oppermann H, Heinrich M, Birkemeyer C, Meixensberger J, Gaunitz F: The proton-coupled oligopeptide transporters PEPT2, PHT1 and PHT2 mediate the uptake of carnosine in glioblastoma cells. Amino Acids. 2019 Jul;51(7):999-1008. doi: 10.1007/s00726-019-02739-w. Epub 2019 May 9. [PubMed:31073693 ]
  11. Heinz LX, Lee J, Kapoor U, Kartnig F, Sedlyarov V, Papakostas K, Cesar-Razquin A, Essletzbichler P, Goldmann U, Stefanovic A, Bigenzahn JW, Scorzoni S, Pizzagalli MD, Bensimon A, Muller AC, King FJ, Li J, Girardi E, Mbow ML, Whitehurst CE, Rebsamen M, Superti-Furga G: TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature. 2020 May;581(7808):316-322. doi: 10.1038/s41586-020-2282-0. Epub 2020 May 13. [PubMed:32433612 ]