scholarly journals Toll-like receptor signalling via IRAK4 confers epithelial integrity and tightness through regulation of junctional tension

2021 ◽  
Author(s):  
Jesse Peterson ◽  
Kinga Balogh Sivars ◽  
Ambra Bianco ◽  
Katja Roeper
Keyword(s):  
Signal Transduction ◽  
Epithelial Cells ◽  
Interleukin 1 ◽  
Toll Like Receptor ◽  
Receptor Signalling ◽  
Epithelial Junctions ◽  
Toll Receptor ◽  
Epithelial State ◽  
Tlr Signalling ◽  
Inhibitor Treatment

Toll-like receptors (TLRs) in mammalian systems are well characterised for their role in innate immunity. In addition, TLRs also fulfil crucial functions outside immunity, including the dorso-ventral patterning function of the original Toll receptor in Drosophila and neurogenesis in mice. Recent discoveries in flies suggested key roles for TLRs in epithelial cells in patterning of cytoskeletal activity near epithelial junctions. Here we address the function of TLRs and the downstream key signal transduction component IRAK4 (interleukin-1 receptor associated kinase 4) in human epithelial cells. Using differentiated human Caco-2 cells as a model for the intestinal epithelium, we show that these cells exhibit baseline TLR signalling as revealed by p-IRAK4 and that blocking IRAK4 function leads to a loss of epithelial tightness involving key changes at tight junctions and adherens junctions. These changes correlate with a loss of epithelial tension and changes in junctional actomyosin. Knock-down of IRAK4 and certain TLRs phenocopies the inhibitor treatment. These data suggest a model whereby TLR receptors near epithelial junctions might be involved in a continuous sensing of the epithelial state to promote epithelial tightness and integrity.

Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2

2008 ◽  
Vol 36 (3) ◽  
pp. 449-452 ◽  
Author(s):  
Andrew G. Bowie
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Relative Role ◽  
Toll Like Receptor ◽  
Turn On ◽  
Receptor Signalling ◽  
Necrosis Factor

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-κB (nuclear factor κB). The TLR pathway to NF-κB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys63 polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-κB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-κB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-κB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-κB activation.

scholarly journals Toll-Like Receptor 4/Spleen Tyrosine Kinase Complex in High Glucose Signal Transduction of Proximal Tubular Epithelial Cells

2015 ◽  
Vol 35 (6) ◽  
pp. 2309-2319 ◽  
Author(s):  
Won Seok Yang ◽  
Joon-Seok Kim ◽  
Nam Jeong Han ◽  
Mee Jeong Lee ◽  
Su-Kil Park
Keyword(s):  
Signal Transduction ◽  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
High Glucose ◽  
Toll Like Receptor ◽  
Tubular Epithelial Cells ◽  
Spleen Tyrosine Kinase ◽  
Toll Like Receptor 4 ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Background/Aims: High glucose activates spleen tyrosine kinase (Syk) in human proximal tubular epithelial cells (HK-2 cells), which leads to NF-κB activation and transforming growth factor-ß1 (TGF-ß1) production. We explored the signal transduction pathway from high glucose to Syk activation. Methods: The pathway was evaluated by siRNA transfection, immunoprecipitation and Western blot. Results: High glucose stimulated Syk activation within 10 min. Depletion of toll-like receptor 4 (TLR4) attenuated high glucose-induced Syk activation, NF-κB p65 nuclear translocation, and TGF-ß1 production. In addition, TLR4 inhibitor (CLI-095), TLR4-neutralizing antibody, and depletion of myeloid differentiation factor 88 (MyD88) all attenuated high glucose-induced Syk activation. As an evidence of TLR4 activation, interleukin-1 receptor-associated kinase 1 was recruited to MyD88 and TLR4 upon exposure to high glucose. Syk was co-immunoprecipitated with TLR4, and Syk bound to TLR4 was activated by high glucose. High-mobility group box-1 (HMGB-1), an endogenous activator of TLR4, rapidly increased in TLR4 immunoprecipitates upon high glucose stimulation, and this association was reduced by N-acetylcysteine, an antioxidant. An HMGB-1 inhibitor glycyrrhizin suppressed high glucose-induced Syk activation. Conclusion: Syk is constitutively associated with TLR4. High glucose induces an immediate, reactive oxygen species-dependent, extracellular release of HMGB-1 which binds to TLR4 and activates it, leading to Syk activation.

All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction

2002 ◽  
Vol 115 (4) ◽  
pp. 679-688 ◽  
Author(s):  
Jee Y. Chung ◽  
Young Chul Park ◽  
Hong Ye ◽  
Hao Wu
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Functional Divergence ◽  
Interleukin 1 ◽  
Tnf Receptor ◽  
Structural Studies ◽  
Toll Like Receptor ◽  
Signal Transducers ◽  
Signaling Specificity ◽  
Necrosis Factor

The tumor necrosis factor (TNF) receptor associated factors (TRAFs) have emerged as the major signal transducers for the TNF receptor superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAFs collectively play important functions in both adaptive and innate immunity. Recent functional and structural studies have revealed the individuality of each of the mammalian TRAFs and advanced our understanding of the underlying molecular mechanisms. Here, we examine this functional divergence among TRAFs from a perspective of both upstream and downstream TRAF signal transduction pathways and of signaling-dependent regulation of TRAF trafficking. We raise additional questions and propose hypotheses regarding the molecular basis of TRAF signaling specificity.

Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4

Nature ◽  
2002 ◽  
Vol 416 (6882) ◽  
pp. 750-754 ◽  
Author(s):  
Nobutaka Suzuki ◽  
Shinobu Suzuki ◽  
Gordon S. Duncan ◽  
Douglas G. Millar ◽  
Teiji Wada ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Toll Like Receptor ◽  
Receptor Signalling ◽  
Severe Impairment

The role of MyD88-like adapters in Toll-like receptor signal transduction

2003 ◽  
Vol 31 (3) ◽  
pp. 643-647 ◽  
Author(s):  
L.A.J. O'Neill
Keyword(s):  
Signal Transduction ◽  
Interleukin 1 ◽  
Adapter Proteins ◽  
Adapter Protein ◽  
Tir Domain ◽  
Receptor Signal ◽  
The Subject ◽  
Tir Domains ◽  
Tlr Signalling

Signal-transduction pathways activated by Toll-like receptors (TLRs) have been the subject of intense investigation because of the key role played by TLRs in the recognition and elimination of microbes. Signalling is initiated by a domain termed the Toll/interleukin-1 (IL-1) receptor (TIR) domain that occurs on the cytosolic face of TLRs. This recruits, via homotypic interactions, adapter proteins that contain TIR domains. Three such adapter proteins have been discovered to date, and have been named MyD88, Mal [MyD88 adapter-like; also known as TIRAP (TIR domain-containing adapter protein)] and Trif (TIR-domain-containing adapter inducing interferon-β). Differences are emerging between TLRs in terms of which adapter is recruited by which TLR. This may lead to specificities in TLR signalling, with pathways being triggered that are specific for the elimination of the invading microbe. However, signals that separate Mal from MyD88 have yet to emerge, although biochemical differences between the two proteins imply that each will have a specific function.

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