Contributions of Unique Intracellular Domains to Switchlike Biosensing by Toll-like Receptor 4

Daringer, Nichole M.; Schwarz, Kelly A.; Leonard, Joshua N.

doi:10.1074/jbc.m114.610063

Cited by 9 publications

(9 citation statements)

References 45 publications

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“…It appears that only the disulfide HMGB1 binds to MD-2, an interaction that is of critical importance for HMGB1-mediated cytokine/chemokine production and the development of subsequent tissue injury [34]. On the other hand, ROS/TLR4-coupled activation could be due to a reversible “atomic” specificity in which specific sulfur atoms on cysteine residues [36, 37] uniquely expressed in the intracellular domains of TLR4 [38] may play a crucial role.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 signaling: A common pathway for interactions between prooxidants and extracellular disulfide high mobility group box 1 (HMGB1) protein-coupled activation

Zhang

Karki

Igwe

2015

Biochemical Pharmacology

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Necrotic cells passively release HMGB1, which can stimulate TLR4 in an autocrine fashion to potentially initiate “sterile” inflammation that maintains different disease states. We have shown that prooxidants can induce NF-κB activation through TLR4 stimulation. We examined whether prooxidants enhance HMGB1-induced TLR4 signaling through NF-κB activation. We used LPS-EK as a specific agonist for TLR4, and PPC and SIN-1 as in situ sources for ROS. As model systems, we used HEK-Blue cells (stably transfected with mouse TLR4), RAW-Blue™ cells (derived from murine RAW 264.7 macrophages) and primary murine macrophages from TLR4-KO mice. Both HEK-Blue and RAW-Blue 264.7 cells express optimized secreted embryonic alkaline phosphatase (SEAP) reporter under the control of a promoter inducible by NF-κB. We treated cells with HMGB1 alone and/or in conjunction with prooxidants and/or inhibitors using SEAP release as a measure of TLR4 stimulation. HMGB1 alone and/or in conjunction with prooxidants increased TNFα and IL-6 released from TLR4-WT, but not from TLR4-KO macrophages. Pro-oxidants increased HMGB1 release, which we quantified by ELISA. We used both fluorescence microscopy imaging and flow cytometry to quantify the expression of intracellular ROS. TLR4-neutralizing antibody decreased prooxidant-induced HMGB1 release. Prooxidants promoted HMGB1-induced NF-κB activation as determined by increased release of SEAP and TNF-α, and accumulation of iROS. HMGB1 (Box A), anti-HMGB1 and anti-TLR4-neutralizing pAbs inhibited HMGB1-induced NF-κB activation, but HMGB1 (Box A) and anti-HMGB1 pAb had no effect on prooxidant-induced SEAP release. The present results confirm that prooxidants enhance proinflammatory effects of HMGB1 by activating NF-κB through TLR4 signaling.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 signaling: A common pathway for interactions between prooxidants and extracellular disulfide high mobility group box 1 (HMGB1) protein-coupled activation

Zhang

Karki

Igwe

2015

Biochemical Pharmacology

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“…LPS binding to MD2 promotes a conformational change that induces TLR4 ectodomain dimerization, leading to dissociation of TIC from TLR4. In the absence of TIC, the TIR domain of TLR4 spontaneously dimerizes and induces adapter recruitment and downstream signaling (16). It has been shown that homoassociation of TLR4 occurs prior to its translocation and clustering to lipid rafts (17).…”

mentioning

confidence: 99%

TRAF3-interacting JNK-activating modulator promotes inflammation by stimulating translocation of Toll-like receptor 4 to lipid rafts

Guan

Wang

et al. 2019

Journal of Biological Chemistry

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Toll-like receptors (TLRs) are key players of the innate immune system and contribute to inflammation and pathogen clearance. Although TLRs have been extensively studied, it remains unclear how exactly bacterial lipopolysaccharide (LPS)induced conformational changes of the extracellular domain of the TLRs trigger the dimerization of their intracellular domain across the plasma membrane and thereby stimulate downstream signaling. Here, using LPS-stimulated THP-1-derived macrophages and murine macrophages along with immunoblotting and immunofluorescence and quantitative analyses, we report that in response to inflammatory stimuli, the coiled-coil protein TRAF3-interacting JNK-activating modulator (T3JAM) associates with TLR4, promotes its translocation to lipid rafts, and thereby enhances macrophage-mediated inflammation. T3JAM overexpression increased and T3JAM depletion decreased TLR4 signaling through both the MyD88-dependent pathway and TLR4 endocytosis. Importantly, deletion or mutation of T3JAM to disrupt its coiled-coil-mediated homoassociation abrogated TLR4 recruitment to lipid rafts. Consistently, T3JAM depletion in mice dampened TLR4 signaling and alleviated LPS-induced inflammatory damage. Collectively, our findings reveal an additional molecular mechanism by which TLR4 activity is regulated and suggest that T3JAM may function as a molecular clamp to "tighten up" TLR4 and facilitate its translocation to lipid rafts. cro ARTICLE 2744

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“…В отсутствие TIC домены TLR4 TIR спонтанно димеризуются и запускают дальнейший сложный каскад реакций в клетке (цит. по [10])…”

Section: рисунок 2 предполагаемая модель передачи сигнала через Tlr4unclassified

Genetic and Molecular Basis of Asymptomatic Bacteriuria in Children: What’s New?

Захарова¹,

Османов²,

Мумладзе³

et al. 2018

Med. sov.

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Contributions of Unique Intracellular Domains to Switchlike Biosensing by Toll-like Receptor 4

Cited by 9 publications

References 45 publications

Toll-like receptor 4 signaling: A common pathway for interactions between prooxidants and extracellular disulfide high mobility group box 1 (HMGB1) protein-coupled activation

Toll-like receptor 4 signaling: A common pathway for interactions between prooxidants and extracellular disulfide high mobility group box 1 (HMGB1) protein-coupled activation

TRAF3-interacting JNK-activating modulator promotes inflammation by stimulating translocation of Toll-like receptor 4 to lipid rafts

Genetic and Molecular Basis of Asymptomatic Bacteriuria in Children: What’s New?

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