The Pharmacology of the SLC15A4-TASL Complex, an Emerging Target for the Treatment of Lupus.

SLC15A4 is a member of the solute carrier superfamily that has been strongly linked to the pathogenesis of the auto-immune disease SLE. The endo-lysosomally localized SLC15A4 has traditionally been considered a proton-dependent histidine and peptide transporter, but has also been shown to facilitate TLR7, 8, and 9 induced IFN-alpha signaling in B cells and pDCs. New research has shown that SLC15A4 facilitates endo-lysosomal TLR signaling through a scaffolding interaction with a newly identified signal transducer, termed TASL. This interaction enables TLR7, 8, and 9 induced IRF5 activation, which is a crucial pathway in the pathogenesis of lupus. SLC15A4 is therefore an attractive target for the development of drugs for the treatment of SLE, and several small molecule SLC15A4 binders have now been reported which are capable of inhibiting TLR7, 8, or 9 signaling. This review summarizes the SLC15A4:TASL complex, its link to SLE, existing evidence for the transporter activity of SLC15A4, the current small molecule binders, and tools available for further drug discovery efforts.