Title: The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid-sensing TLRs and ligands to endolysosomes.

Authors: Rimann, Ivo; Gonzalez-Quintial, Rosana; Baccala, Roberto; Kiosses, William B; Teijaro, John R; Parker, Christopher G; Li, Xiaohong; Beutler, Bruce; Kono, Dwight H; Theofilopoulos, Argyrios N

Published In Proc Natl Acad Sci U S A, (2022 Apr 05)

Abstract: A function-impairing mutation (feeble) or genomic deletion of SLC15A4 abolishes responses of nucleic acid–sensing endosomal toll-like receptors (TLRs) and significantly reduces disease in mouse models of lupus. Here, we demonstrate disease reduction in homozygous and even heterozygous Slc15a4 feeble mutant BXSB male mice with a Tlr7 gene duplication. In contrast to SLC15A4, a function-impairing mutation of SLC15A3 did not diminish type I interferon (IFN-I) production by TLR-activated plasmacytoid dendritic cells (pDCs), indicating divergence of function between these homologous SLC15 family members. Trafficking to endolysosomes and function of SLC15A4 were dependent on the Adaptor protein 3 (AP-3) complex. Importantly, SLC15A4 was required for trafficking and colocalization of nucleic acid–sensing TLRs and their ligands to endolysosomes and the formation of the LAMP2+VAMP3+ hybrid compartment in which IFN-I production is initiated. Collectively, these findings define mechanistic processes by which SLC15A4 controls endosomal TLR function and suggest that pharmacologic intervention to curtail the function of this transporter may be a means to treat lupus and other endosomal TLR-dependent diseases.

PubMed ID: 35349343

MeSH Terms: Animals; Endosomes/metabolism; Ligands; Lysosomes/metabolism; Membrane Transport Proteins/genetics; Mice; Nucleic Acids*; Toll-Like Receptors/metabolism