{"doi":"10.1073/pnas.2200544119","title":"The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes","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.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":246213,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":882767,"name":"Rosana González‐Quintial","orcid":null,"position":1,"is_corresponding":false},{"id":882028,"name":"Roberto Baccalà","orcid":"0000-0002-3159-8469","position":2,"is_corresponding":false},{"id":324391,"name":"William B. Kiosses","orcid":"0000-0003-1832-9050","position":3,"is_corresponding":false},{"id":262640,"name":"John R. Teijaro","orcid":"0000-0001-8280-8887","position":4,"is_corresponding":false},{"id":116745,"name":"Christopher G. Parker","orcid":"0000-0001-8509-9289","position":5,"is_corresponding":false},{"id":364915,"name":"Xiaohong Li","orcid":"0000-0001-8357-5587","position":6,"is_corresponding":false},{"id":51949,"name":"Bruce Beutler","orcid":"0000-0002-3639-246X","position":7,"is_corresponding":false},{"id":135554,"name":"Dwight H. Kono","orcid":null,"position":8,"is_corresponding":false},{"id":882768,"name":"Argyrios N. Theofilopoulos","orcid":null,"position":9,"is_corresponding":false},{"id":882766,"name":"Ivo Rimann","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:23:43.438539Z","pmid":"35349343","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}