Quantitative single-molecule imaging of TLR4 reveals ligand-specific receptor dimerization

Science Signaling
Carmen L KrügerMike Heilemann

Abstract

In humans, invading pathogens are recognized by Toll-like receptors (TLRs). Upon recognition of lipopolysaccharide (LPS) derived from the cell wall of Gram-negative bacteria, TLR4 dimerizes and can stimulate two different signaling pathways, the proinflammatory, MyD88-dependent pathway and the antiviral, MyD88-independent pathway. The balance between these two pathways is ligand-dependent, and ligand composition determines whether the invading pathogen activates or evades the host immune response. We investigated the dimerization behavior of TLR4 in intact cells in response to different LPS chemotypes through quantitative single-molecule localization microscopy. Quantitative superresolved data showed that TLR4 was monomeric in the absence of its co-receptors MD2 and CD14 in transfected HEK 293 cells. When TLR4 was present together with MD2 and CD14 but in the absence of LPS, 52% of the receptors were monomeric and 48% were dimeric. LPS from Escherichia coli or Salmonella minnesota caused the formation of dimeric TLR4 complexes, whereas the antagonistic LPS chemotype from Rhodobacter sphaeroides maintained TLR4 in monomeric form at the cell surface. Furthermore, we showed that LPS-dependent dimerization was required for the acti...Continue Reading

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Citations

Dec 14, 2018·Methods and Applications in Fluorescence·K S GruβmayerD-P Herten
Jan 16, 2020·International Journal of Molecular Sciences·Lalita Mazgaeen, Prajwal Gurung
Dec 11, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yang HuLi Xu
Apr 11, 2019·Molecular Biology of the Cell·Tim N BalderingMike Heilemann
Mar 7, 2020·Journal of Cell Science·Lai WenKlaus Ley
Jan 21, 2021·Animals : an Open Access Journal From MDPI·Efstathios Sarmikasoglou, Antonio P Faciola
Nov 27, 2020·Current Opinion in Structural Biology·Huanhuan ChenTai-Yen Chen
Mar 2, 2018·Journal of Medicinal Chemistry·Fabio A FacchiniFrancesco Peri
Sep 20, 2021·Journal of Molecular Biology·Dipika NandiAshish Kulkarni

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