{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:51:23Z","timestamp":1791226283138,"version":"4.1.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI150157"],"award-info":[{"award-number":["R01AI150157"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014731","name":"Global Lyme Alliance","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100014731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Toll-like receptor 2\/1 (TLR2\/1) heterodimers detect triacylated lipoproteins. Although TLR2\/1 complexes localize to both the plasma membrane and endosome, the functional contributions of compartment-specific signaling are not completely defined. A common human TLR1 polymorphism (rs5743618), at which one allele substitutes isoleucine for serine adjacent to the transmembrane domain, restricts TLR1 intracellularly and is associated with an increased risk of antibiotic-refractory Lyme arthritis. This mis-localization provides a model to examine how receptor positioning influences downstream signaling. Here, we investigated the rs5743618 polymorphism\u2019s effects on TLR1 localization and compartment-specific NF-\u03baB activation. Using a CD14+\u2009TLR2+\u2009HEK cell reporter system that enables transient expression of both allelic variants, we confirmed that the polymorphism is excluded from the cell surface and retained intracellularly, whereas the ancestral allele localizes to both compartments. Functionally, the ancestral allele signaled from both compartments, while the derived allele signaled exclusively from endosomes. Spatially restricted signaling exhibited influence on IkB\u03b1 degradation and NF-\u03baB activation compared with the ancestral allele. This activation was dependent on MyD88 localized at ligand-containing endosomes, establishing a role for this adapter in intracellular TLR2\/1 signaling. These findings provide insight into how this common polymorphism impacts inflammatory outcomes.<\/jats:p>","DOI":"10.1371\/journal.pone.0358252","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:59:41Z","timestamp":1791223181000},"page":"e0358252","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endosome restricted human TLR1 polymorphism highlights a role for MyD88 in Pam3CSK4 detection"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-8546","authenticated-orcid":true,"given":"Christopher C.","family":"Wells","sequence":"first","affiliation":[{"name":"Tufts Graduate School of Biomedical Sciences","place":["Boston, Massachusetts, United States of America"],"department":["Graduate Program in Immunology"]},{"name":"Tufts University School of Medicine","place":["Boston, Massachusetts, United States of 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