Negative Regulation of Toll-like Receptor-mediated Signaling by Tollip*

By Guolong Zhang, S. Ghosh. Journal of Biological Chemistry, 2002

635 citations recorded by the source corpus.

Toll-like receptor (TLR)-mediated recognition of pathogens represents one of the most important mechanisms of innate immunity and disease resistance. The adaptor protein Tollip was identified initially as an intermediate in interleukin (IL)-1 signaling. Here we report that Tollip also associates directly with TLR2 and TLR4 and plays an inhibitory role in TLR-mediated cell activation. Inhibition by Tollip is mediated through its ability to potently suppress the activity of IL-1 receptor-associated kinase (IRAK) after TLR activation. In addition, we show for the first time that Tollip is a bona fidesubstrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1. Negative regulation of TLR signaling by Tollip may therefore serve to limit the production of proinflammatory mediators during inflammation and infection.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/56f463796a88c80117a2a1235686061cc9971964

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Shizuo Akira
2. S. Ghosh
3. M. Hayden
4. K. Takeda
5. Luke A. O'Neill
6. A. West
7. T. Kaisho
8. S. Lehnardt

In Immunology

1. Shizuo Akira
2. S. Ghosh
3. Luke A. O'Neill
4. M. Hayden
5. K. Takeda
6. A. West
7. T. Kaisho
8. S. Lehnardt

In Molecular Biology

1. Luke A. O'Neill
2. M. Hayden
3. S. Ghosh
4. Shizuo Akira
5. K. Takeda
6. M. Abreu
7. S. Lehnardt
8. Carol A. Colton

Citations in the corpus

• Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain (2009, background): “Competition between functional and nonfunctional adaptor proteins such as MyD88 and a splice variant of MyD88 (MyD88s) has been shown to reduce TLR signaling, while adaptor proteins such as Toll inhibitor protein, which sequester a corresponding signaling protein, also downregulate proinflammatory s”
• Mechanisms of Selective Autophagy (2016, neutral): “Given that many cargo receptors form dimers or multimers and/or contain multiple LIR motifs, avidity-driven interactions with membrane-localized Atg8-family proteins are likely to be a more general property of cargo receptors [30,49,56,84,91 – 94].”
• TLR signaling pathways. (2004, background): “Subsequently, Tollip has been shown to negatively regulate the TLR-mediated signaling pathway[30,31].”
• NF-κB and the immune response (2006, background): “Tollip, an adapter protein constitutively associated with IRAK, is phosphorylated and dissociates following IRAK4 activation (Burns et al., 2000; Zhang and Ghosh, 2002).”
• Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function (2010, background): “Toll-interacting protein ( TOLLIP ) is an intracellular protein that inhibits TLR2 and TLR4 signalling through its effect on IL-1R-associated kinases (IRAKs”
• Toll-like receptor signalling (2004, background): “Subsequently, it has been shown to associate directly with the cytoplasmic TIR domain of IL-1Rs, TLR2 and TLR4, following the stimulation of these receptors, and to inhibit TLR-mediated cellular responses by suppressing the phosphorylation and kinase activity of IRAK1 (Ref”
• Toll-like receptors. (2003, background): “A subsequent study showed that Tollip negatively regulates the TLR-mediated signaling pathway (224, 225).”
• Innate immunity and neuroinflammation in the CNS: The role of microglia in Toll‐like receptor‐mediated neuronal injury (2009, background): “The suggested negative regulators involved include IL-10, which blocks the production of inflammatory cytokines (Moore et al., 2001) and downregulates TLR4 expression (Muzio et al., 2000), as well as intracellular feedback inhibitors of the TLR pathway, such as Tollip (Zhang and Ghosh, 2002) or the ”
• Lipopolysaccharide signaling in endothelial cells (2006, background): “145 Tollip has also been shown to associate with TLR4 and is phosphorylated by IRAK following stimulation with LPS”
• The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense (2000, background): “Tollip was found to associate with the TIR-domain of the IL-RAcP and, more recently, TLRs 2 and 4 (50).”