2.A.17.3.11
Solute carrier family 15 member 4 (Peptide transporter 4) (Peptide/histidine transporter 1) (hPHT1; SLC15A4; ) is present in immune cells (Verri et al. 2016). It is a 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 responses (Bhardwaj et al. 2006, Kobayashi et al. 2014, Song et al. 2018). It is able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans peptides (Song et al. 2018; Oppermann et al. 2019). Transport activity is pH-dependent and maximized in the acidic lysosomal environment. It is involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycan fragments across the endolysosomal membrane: it catalyzes the transport of certain bacterial peptidoglycan-derived peptides, such as muramyl dipeptide, the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand (Kobayashi et al. 2014, Song et al. 2018). Byrnes et al. 2022 reviewed three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. PHT1 is a histidine/oligopeptide transporter with an essential role in Toll-like receptor innate immune responses. It can act as a receptor by recruiting the adaptor protein TASL which leads to type I interferon production via IRF5 (Custódio et al. 2023). Persistent stimulation of this signalling pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). The authors presented the Cryo-EM structure of PHT1 stabilized in the outward-open conformation and proposed a model of the PHT1-TASL complex, in which the first 16 N-terminal TASL residues that fold into a helical structure that binds in the central cavity of the inward-open conformation of PHT1. This work suggests the molecular basis of PHT1/TASL mediated type I interferon production (Custódio et al. 2023). PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates have been characterized (Pujol-Giménez et al. 2024).