Different functional role of domain boundaries of Toll-like receptor 4

Treeby, Mireille; Vašl, Jožica; Ota, Peter; Friedrich, Jožica; Jerala, Roman

doi:10.1016/j.bbrc.2009.02.017

Cited by 15 publications

(15 citation statements)

References 32 publications

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“…Other CSs/Di-CSs are also likely to interact with TLRs via their cysteine-rich domains. 36,[44][45][46][47][48][49][50][51] This interaction possibly affects the binding of TLRs with their ligands, thereby weakening the IL-6 secretion triggered by the activation of TLRs, as shown in Figs. 2, 3, and 5.…”

Section: Discussionmentioning

confidence: 99%

Effects of Chondroitin Sulfate and Its Oligosaccharides on Toll-Like Receptor-Mediated IL-6 Secretion by Macrophage-Like J774.1 Cells

Jin

Iwamoto

Yamada

et al. 2011

Bioscience, Biotechnology, and Biochemistry

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The effects of two types of chondroitin sulphate (CS), CS-A and CS-C, their oligosaccharides (oligo-CSs), and disaccharides (Di-CSs) on toll-like receptor (TLR)-mediated secretion of interleukin (IL)-6 were compared using macrophage-like cell line J774.1. IL-6 secretion in the J774.1 cells was markedly increased by Pam3CS4, LPS, and CpG, the ligands to TLR1/2, 4, and 9 respectively. Among these three ligands, CpG-induced IL-6 was most clearly suppressed by CSs and their digests. Suppression of IL-6 secretion by smaller sized CS-A was stronger than that by intact CS-A, whereas no such size-dependent suppression was apparent for CS-C. Di-4S, the disaccharide unit of the CS-A digest, also showed much stronger suppression than Di-6S, the disaccharide unit of the CS-C digest, and the non-sulfated disaccharide unit, Di-0S. The suppressing activity of oligo-CSs, particularly Di-CSs, against TLR-mediated inflammation was dependent on the CS structure, including the sulfation site.

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Section: Discussionmentioning

confidence: 99%

Effects of Chondroitin Sulfate and Its Oligosaccharides on Toll-Like Receptor-Mediated IL-6 Secretion by Macrophage-Like J774.1 Cells

Jin

Iwamoto

Yamada

et al. 2011

Bioscience, Biotechnology, and Biochemistry

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“…Electrostatic repulsion because of the pattern of charged residues may be involved, although the net charge of this segment is only slightly negative. Nevertheless, we have shown previously that insertion of a peptide linker between the TLR4 ectodomain and the transmembrane domain decreases receptor activation, which could be due to the interaction of the ectodomain with the membrane surface (57). It has been discovered recently that the TLR4 ectodomain is cross-linked by nickel ions mediated by nonconserved histidine residues, contributing to the nickel allergy (60).…”

Section: Discussionmentioning

confidence: 99%

The Ectodomain of the Toll-like Receptor 4 Prevents Constitutive Receptor Activation

Panter

Jerala

2011

Journal of Biological Chemistry

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Toll-like receptor 4 (TLR4) is involved in activation of the innate immune response in a large number of different diseases.Despite numerous studies, the role of separate domains of TLR4 in the regulation of receptor activation is poorly understood. Replacement of the TLR4 ectodomain with LPS-binding proteins MD-2 or CD14 resulted in a robust ligand-independent constitutive activation comparable with the maximal stimulation of the receptor with LPS. The same effect was achieved by the replacement of the ectodomain with a monomeric fluorescent protein or a 24-kDa gyrase B fragment. This demonstrates an intrinsic dimerization propensity of the transmembrane and cytoplasmic domains of TLR4 and reveals a previously unknown function of the ectodomain in inhibiting spontaneous receptor dimerization. Constitutive activation was abolished by the replacement of the ectodomain by a bulkier protein ovalbumin. N-terminal deletion variants of TLR4 revealed that the smallest segment of the ectodomain that already prevents constitutive activity comprises only 90 residues (542 to 631) of the total 608 residues. We conclude that TLR4 represents a receptor with a low threshold of activation that can be rapidly activated by the release of inhibition exerted by its ectodomain. This is important for the sensitivity of TLR4 to activation by different agonists. The TLR4 ectodomain has multiple roles in enabling ligand regulated activation, providing proper localization while serving as an inhibitor to prevent spontaneous, ligand-independent dimerization.Pattern recognition receptors are proteins expressed by cells of the innate immune system and act as a first line of host defense against invading microorganisms, recognizing diverse but highly conserved structural pathogen-associated molecular patterns of bacteria, fungi, and viruses (1). Activation of pattern recognition receptors by their respective ligands triggers an immediate immune response, characterized by proinflammatory cytokine production (1, 2). Toll-like receptors (TLRs) 2 are a family of pattern recognition receptors central to the vertebrate innate immune response. Activation of TLRs links innate and adaptive immunity through proinflammatory signaling and induction of costimulatory molecules on immune cells (3, 4). However, activation of TLRs has to be a tightly regulated process. TLRs have to be able to mount an immediate immune response upon binding of the agonist, whereas in the absence of the ligand it is imperative that they remain in an inactive state to prevent unwanted activation that may lead to excessive inflammation and autoimmune disease (5). This is especially important for TLR4, the cellular receptor for LPS, a molecular signature of the outer cell membrane of Gram-negative bacteria (6). Activation of TLR4 by LPS affects the regulation of more than 1000 genes (7). Additionally, TLR4 signaling has been implicated in sterile inflammation through activation of the receptor by endogenous ligands (8 -14).TLR4 is a type I transmembrane glycoprotein. The ectodoma...

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“…However, a slightly smaller construct in which the ECD comprised LRR22 and LRRCT (TLR4 ⌬563) exhibited constitutive signaling. A final observation that challenges the steric occlusion model is that inserting linkers between the TMD and ECD domain of TLR4 decreased LPS-inducible signaling but did not lead to constitutive signaling (44).…”

Section: Discussionmentioning

confidence: 99%

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

Daringer¹,

Schwarz²,

Leonard³

2015

Journal of Biological Chemistry

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Background: TLR4 is an important receptor, promoting both protective immunity and inflammatory diseases. Results: A revised model of TLR4 signaling is proposed, based upon new observations. Conclusion: TLR4 forms an autoinhibitory complex in the absence of ligand; disrupting this complex induces downstream signaling.Significance: This new mechanism may explain TLR4 responsiveness to diverse ligands and guide the design of novel therapeutics.

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Different functional role of domain boundaries of Toll-like receptor 4

Cited by 15 publications

References 32 publications

Effects of Chondroitin Sulfate and Its Oligosaccharides on Toll-Like Receptor-Mediated IL-6 Secretion by Macrophage-Like J774.1 Cells

Effects of Chondroitin Sulfate and Its Oligosaccharides on Toll-Like Receptor-Mediated IL-6 Secretion by Macrophage-Like J774.1 Cells

The Ectodomain of the Toll-like Receptor 4 Prevents Constitutive Receptor Activation

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

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