The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Article numbere2200544119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - Apr 5 2022


  • AP-3
  • IFN-I
  • SLC15 solute carriers
  • lupus
  • nucleic acid–sensing TLRs

ASJC Scopus subject areas

  • General


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