Peptide transporter 4 | SLC15 family of peptide transporters | IUPHAR Guide to IMMUNOPHARMACOLOGY

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Peptide transporter 4

  Target has curated data in GtoImmuPdb

Target id: 987

Nomenclature: Peptide transporter 4

Abbreviated Name: PHT1

Systematic Nomenclature: SLC15A4

Family: SLC15 family of peptide transporters

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - - SLC15A4 solute carrier family 15 member 4
Mouse - - Slc15a4 solute carrier family 15, member 4
Rat - - Slc15a4 solute carrier family 15 member 4
Previous and Unofficial Names
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
Specialist databases
Bioparadigms SLC Tables SLC15A4 (Hs)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
Substrates and Reaction Kinetics
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
muramyl dipeptide Hs - - 7,9
His-Leu-lopinavir Hs - - 6
glycyl-sarcosine Hs - - 1,3,9,11
MDP-rhodamine Hs - - 2,7
Tri-DAP Hs - - 5,8-9
C12-iE-DAP Hs - - 5
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 [1,4,6,12,14] and the model peptide used, i.e., carnosine [1,14], suggest a similar mode of operation as PEPT1 and PEPT2 proteins.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[14C]histidine Hs Binding - - 12-14
[3H]histidine Hs - - - 1,6,11-12
Immunopharmacology Comments
SLC15A4 is an oligopeptide transporter that is expressed in early endosomes, and which is involved in NOD1-dependent NF-κB signaling [5]. 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 [7,10].
Cell Type Associations
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
References:  7
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS


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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. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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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