ArticlePloS one2013
Inefficient TLR4/MD-2 heterotetramerization by monophosphoryl lipid A.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- Structural insight into TLR4/MD-2 activation by synthetic LPS mimetics with distinct binding modes.Nature communications · 2025Article
- Characterization of Turbo, a TLR Ligand-based Adjuvant for Glycoconjugate Vaccines.ImmunoHorizons · 2024Article
- Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue.International immunology · 2024Article
- Therapeutic Targeting of TLR4 for Inflammation, Infection, and Cancer: A Perspective for Disaccharide Lipid A Mimetics.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Rational Vaccine Design in Times of Emerging Diseases: The Critical Choices of Immunological Correlates of Protection, Vaccine Antigen and Immunomodulation.Pharmaceutics · 2021Review
- Article
- Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics.Frontiers in immunology · 2021Article
- Natural and synthetic carbohydrate-based vaccine adjuvants and their mechanisms of action.Nature reviews. Chemistry · 2021Review
- Toll-like receptor 4-mediated inflammation triggered by extracellular IFI16 is enhanced by lipopolysaccharide binding.PLoS pathogens · 2020Article
- Toll-like receptor 4 and protease-activated receptor 2 in physiology and pathophysiology of the nervous system: more than just receptor cooperation?Neural regeneration research · 2019Article
- Application of a TLR overexpression cell model in pyrogen detection.Biotechnology and bioengineering · 2019Article
- Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics.Chemical science · 2018Article
- Aminosugar-based immunomodulator lipid A: synthetic approaches.Beilstein journal of organic chemistry · 2018Review
- Funiculosin variants and phosphorylated derivatives promote innate immune responses via the Toll-like receptor 4/myeloid differentiation factor-2 complex.The Journal of biological chemistry · 2017Article
- Monophosphoryl lipid A-induced pro-inflammatory cytokine expression does not require CD14 in primary human dendritic cells.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2016Article
- Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response.Scientific reports · 2015Article
- Kdo2 -lipid A: structural diversity and impact on immunopharmacology.Biological reviews of the Cambridge Philosophical Society · 2015Review
- Development of αGlcN(1↔1)αMan-based lipid A mimetics as a novel class of potent Toll-like receptor 4 agonists.Journal of medicinal chemistry · 2014Article
- Contribution of TLR4 and MyD88 for adjuvant monophosphoryl lipid A (MPLA) activity in a DNA prime-protein boost HIV-1 vaccine.Vaccine · 2014Article
- Novel synthetic toll-like receptor 4/MD2 ligands attenuate sterile inflammation.The Journal of pharmacology and experimental therapeutics · 2014Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Synthetic forms of E. coli monophosphoryl lipid A (sMLA) weakly activate the MyD88 (myeloid differentiation primary response protein) branch of the bifurcated TLR4 (Toll-like receptor 4) signaling pathway, in contrast to diphosphoryl lipid A (sDLA), which is a strong activator of both branches of TLR4. sMLA's weak MyD88 signaling activity is apparent downstream of TLR4/MyD88 signaling as we show that sMLA, unlike sDLA, is unable to efficiently recruit the TNF receptor-associated factor 6 (TRAF6) to the Interleukin-1 receptor-associated kinase 1 (IRAK1). This reduced recruitment of TRAF6 explains MLA's lower MAPK (Mitogen Activated Protein Kinase) and NF-κB activity. As further tests of sMLA's ability to activate TLR4/Myeloid differentiation factor 2 (MD-2), we used the antibody MTS510 as an indicator for TLR4/MD-2 heterotetramer formation. Staining patterns with this antibody indicated that sMLA does not effectively drive heterotetramerization of TLR4/MD-2 when compared to sDLA. However, a F126A mutant of MD-2, which allows lipid A binding but interferes with TLR4/MD-2 heterotetramerization, revealed that while sMLA is unable to efficiently form TLR4/MD-2 heterotetramers, it still needs heterotetramer formation for the full extent of signaling it is able to achieve. Monophosphoryl lipid A's weak ability to form TLR4/MD-2 heterotetramers was not restricted to synthetic E. coli type because cells exposed to a biological preparation of S. minnesota monophosphoryl lipid A (MPLA) also showed reduced TLR4/MD-2 heterotetramer formation. The low potency with which sMLA and MPLA drive heterotetramerization of TLR4/MD-2 contributes to their weak MyD88 signaling activities.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.