Solute carrier family 15 member 4 (SLC15A4)

SLC15A4 encodes a lysosomal/endolysosomal transporter for L-histidine and small oligopeptides, utilizing a proton gradient to drive substrate movement from the lysosomal lumen to the cytosol[1][2][3][5]. It contains 12 transmembrane domains characteristic of the major facilitator superfamily. Uniquely, SLC15A4 also acts as a scaffold, recruiting the adaptor protein TASL in lysosomes to enable activation of IRF5, a transcription factor in the TLR7/8/9 innate immune signaling pathway[1][2]. Genetic or pharmacological disruption of SLC15A4 impairs IRF5 activation, leading to reduced type I interferon and cytokine production[2]. This makes SLC15A4 a potential therapeutic target for inflammatory and autoimmune diseases, notably systemic lupus erythematosus[2][3]. Peptide-like drugs and bacterial peptidoglycan components (MDP, Tri-DAP) are among its known substrates, and competitive inhibition has been demonstrated in cellular models[3]. No approved drugs directly target SLC15A4, but emerging structural data provide avenues for small molecule inhibitor development that could modulate its role in both peptide transport and immune signaling[2].

Other names

Peptide/histidine transporter 1PHT1PTR4FP12591hPHT1Peptide transporter 4Peptide-histidine transporter 4

Small molecule inhibition (investigational; potential for blocking TASL recruitment or substrate transport) and competitive substrate inhibition (by di/tripeptides and peptide-like compounds).