8jzr

Structural highlights

Function

S15A4_HUMAN 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).[UniProtKB:O09014][UniProtKB:Q91W98]^{[1] [2] [3] [4] [5]}

References

1. ↑ 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. PMID:16289537 doi:10.1016/j.ejps.2005.09.014
2. ↑ 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. PMID:25238095 doi:10.1016/j.immuni.2014.08.011
3. ↑ 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. PMID:29224352 doi:10.1021/acs.molpharmaceut.7b00728
4. ↑ 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. PMID:31073693 doi:10.1007/s00726-019-02739-w
5. ↑ Heinz LX, Lee J, Kapoor U, Kartnig F, Sedlyarov V, Papakostas K, César-Razquin A, Essletzbichler P, Goldmann U, Stefanovic A, Bigenzahn JW, Scorzoni S, Pizzagalli MD, Bensimon A, Müller 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. PMID:32433612 doi:10.1038/s41586-020-2282-0
6. ↑ Chen X, Xie M, Zhang S, Monguió-Tortajada M, Yin J, Liu C, Zhang Y, Delacrétaz M, Song M, Wang Y, Dong L, Ding Q, Zhou B, Tian X, Deng H, Xu L, Liu X, Yang Z, Chang Q, Na J, Zeng W, Superti-Furga G, Rebsamen M, Yang M. Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling. Nat Commun. 2023 Oct 20;14(1):6627. PMID:37863913 doi:10.1038/s41467-023-42210-9