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Peer-reviewedCC BY 4.0PLOS One

Endosome restricted human TLR1 polymorphism highlights a role for MyD88 in Pam₃CSK₄ detection

  • Christopher C. Wells1
  • Jeffrey S. Bourgeois2
  • Morgan A. Williams3
  • Klemen Strle4
  • Linden T. Hu
  • Tanja Petnicki-Ocwieja
4 affiliations
  1. 1Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, Massachusetts, United States of America
  2. 2Tufts Lyme Disease Initiative, Tufts University School of Medicine, Boston, Massachusetts, United States of America
  3. 3Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, Massachusetts, United States of America
  4. 4Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
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Abstract

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’s effects on TLR1 localization and compartment-specific NF-κB activation. Using a CD14+ TLR2+ HEK 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 IkBα degradation and NF-κB 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.

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Cite

BibTeXRIS
BibTeX
@article{wells2026endosome,
  title = {{Endosome restricted human TLR1 polymorphism highlights a role for MyD88 in Pam₃CSK₄ detection}},
  author = {Christopher C. Wells and Jeffrey S. Bourgeois and Morgan A. Williams and Klemen Strle and Linden T. Hu and Tanja Petnicki-Ocwieja},
  journal = {PLOS One},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pone.0358252},
  url = {https://doi.org/10.1371/journal.pone.0358252},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Endosome restricted human TLR1 polymorphism highlights a role for MyD88 in Pam₃CSK₄ detection
AU  - Christopher C. Wells
AU  - Jeffrey S. Bourgeois
AU  - Morgan A. Williams
AU  - Klemen Strle
AU  - Linden T. Hu
AU  - Tanja Petnicki-Ocwieja
PY  - 2026
DA  - 2026/10/05
JO  - PLOS One
DO  - 10.1371/journal.pone.0358252
UR  - https://doi.org/10.1371/journal.pone.0358252
AB  - 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’s effects on TLR1 localization and compartment-specific NF-κB activation. Using a CD14+ TLR2+ HEK 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 IkBα degradation and NF-κB 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.
SN  - 1932-6203
ER  -