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Peptide transporter 4

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Target id: 987

Nomenclature: Peptide transporter 4

Abbreviated Name: PHT1

Systematic Nomenclature: SLC15A4

Family: SLC15 family of peptide transporters

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 12 577 12q24.33 SLC15A4 solute carrier family 15 member 4
Mouse 12 574 5 G1.2 Slc15a4 solute carrier family 15, member 4
Rat 12 572 12q14 Slc15a4 solute carrier family 15 member 4
Previous and Unofficial Names Click here for help
PHT1 | solute carrier family 15 member 4 | Peptide/histidine transporter 1 | solute carrier family 15 (oligopeptide transporter), member 4 | solute carrier family 15
Database Links Click here for help
Specialist databases
Bioparadigms SLC Tables SLC15A4 (Hs)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
valacyclovir Hs - - 1
muramyl dipeptide Hs - - 8,10
His-Leu-lopinavir Hs - - 7
glycyl-sarcosine Hs - - 1,4,10,12
MDP-rhodamine Hs - - 3,8
Tri-DAP Hs - - 6,9-10
C12-iE-DAP Hs - - 6
Stoichiometry Click here for help
PHT1 has not been analyzed systematically with respect to driving force, mode of transport, and substrate specificity. The pH dependence observed for transport of histidine [1,5,7,13,15] and the model peptide used, i.e., carnosine [1,15], suggest a similar mode of operation as PEPT1 and PEPT2 proteins.

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Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AJ2-30 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 5.7 pIC50 2
pIC50 5.7 (IC50 1.8x10-6 M) [2]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[14C]histidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Binding - - 13-15
[3H]histidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs - - - 1,7,12-13
Immunopharmacology Comments
SLC15A4 is an oligopeptide transporter that is expressed in early endosomes. It is critical for signalling via certain pattern recognition receptors (e.g. Toll-like receptors 7-9 and NOD receptors) in immune cell subsets [6]. SLC15A4 is associated with autoimmune conditions in humans. SLC15A3 and SLC15A4 are preferentially expressed by cells within the lymphatic system, including dendritic cells. Expression of these two genes is upregulated in response to TLR stimulation [8,11].
Cell Type Associations
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
References:  8
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cellular signalling


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1. Bhardwaj RK, Herrera-Ruiz D, Eltoukhy N, Saad M, Knipp GT. (2006) The functional evaluation of human peptide/histidine transporter 1 (hPHT1) in transiently transfected COS-7 cells. Eur J Pharm Sci, 27 (5): 533-42. [PMID:16289537]

2. Chiu TY, Lazar DC, Wang WW, Wozniak JM, Jadhav AM, Li W, Gazaniga N, Theofilopoulos AN, Teijaro JR, Parker CG. (2024) Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity. Nat Chem Biol, [Epub ahead of print]. [PMID:38191941]

3. Hu Y, Song F, Jiang H, Nuñez G, Smith DE. (2018) SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain-Dependent Immune Response in Mouse Bone Marrow-Derived Macrophages. J Immunol, 201 (2): 652-662. [PMID:29784761]

4. Hu Y, Xie Y, Keep RF, Smith DE. (2014) Divergent developmental expression and function of the proton-coupled oligopeptide transporters PepT2 and PhT1 in regional brain slices of mouse and rat. J Neurochem, 129 (6): 955-65. [PMID:24548120]

5. Kobayashi T, Shimabukuro-Demoto S, Yoshida-Sugitani R, Furuyama-Tanaka K, Karyu H, Sugiura Y, Shimizu Y, Hosaka T, Goto M, Kato N et al.. (2014) The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity, 41 (3): 375-88. [PMID:25238095]

6. Lee J, Tattoli I, Wojtal KA, Vavricka SR, Philpott DJ, Girardin SE. (2009) pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling. J Biol Chem, 284 (35): 23818-29. [PMID:19570976]

7. Mandal A, Pal D, Mitra AK. (2016) Circumvention of P-gp and MRP2 mediated efflux of lopinavir by a histidine based dipeptide prodrug. Int J Pharm, 512 (1): 49-60. [PMID:27543355]

8. Nakamura N, Lill JR, Phung Q, Jiang Z, Bakalarski C, de Mazière A, Klumperman J, Schlatter M, Delamarre L, Mellman I. (2014) Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature, 509 (7499): 240-4. [PMID:24695226]

9. Sasawatari S, Okamura T, Kasumi E, Tanaka-Furuyama K, Yanobu-Takanashi R, Shirasawa S, Kato N, Toyama-Sorimachi N. (2011) The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. Gastroenterology, 140 (5): 1513-25. [PMID:21277849]

10. Song F, Hu Y, Wang Y, Smith DE, Jiang H. (2018) Functional Characterization of Human Peptide/Histidine Transporter 1 in Stably Transfected MDCK Cells. Mol Pharm, 15 (2): 385-393. [PMID:29224352]

11. Song F, Yi Y, Li C, Hu Y, Wang J, Smith DE, Jiang H. (2018) Regulation and biological role of the peptide/histidine transporter SLC15A3 in Toll-like receptor-mediated inflammatory responses in macrophage. Cell Death Dis, 9 (7): 770. [PMID:29991810]

12. Tai W, Chen Z, Cheng K. (2013) Expression profile and functional activity of peptide transporters in prostate cancer cells. Mol Pharm, 10 (2): 477-87. [PMID:22950754]

13. Wang XX, Hu Y, Keep RF, Toyama-Sorimachi N, Smith DE. (2017) A novel role for PHT1 in the disposition of l-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice. Biochem Pharmacol, 124: 94-102. [PMID:27845049]

14. Wang XX, Li YB, Feng MR, Smith DE. (2018) Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice. Pharm Res, 35 (1): 19. [PMID:29305823]

15. Yamashita T, Shimada S, Guo W, Sato K, Kohmura E, Hayakawa T, Takagi T, Tohyama M. (1997) Cloning and functional expression of a brain peptide/histidine transporter. J Biol Chem, 272 (15): 10205-11. [PMID:9092568]


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