New insights into the regulation of TLR signaling.

School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
Journal of Leukocyte Biology (Impact Factor: 4.3). 09/2006; 80(2):220-6. DOI: 10.1189/jlb.1105672
Source: PubMed

ABSTRACT Toll-like receptor (TLR) activation is dictated by a number of factors including the ligand itself and the localization of the receptor, in terms of expression profile and subcellular localization and the signal transduction pathway that has been activated. Recent work into TLR signal transduction has revealed complex regulation at a number of different levels including regulation by phosphorylation, targeted degradation, and sequestration of signaling molecules. Here, we describe recent advances that have been made in our understanding of how TLR signaling is regulated at the biochemical level.

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Available from: Sinead M Miggin, Jul 30, 2015
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    • "Z. Xiang et al. / Fish & Shellfish Immunology 36 (2014) 83e89 86 [27]. Another possible AP-1 activation pathway includes, IRAK through TRAF6 activation of JNK kinases to active Jun, which, in turn, induces the expression of pro-inflammatory cytokines such as TNF, IL-1b, IL-18, and IL-6 [28]. "
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    ABSTRACT: Growing evidence suggests that the transcription factor activator protein-1 (AP-1), a downstream target of mitogen-activated protein kinase (MAPK) signaling, plays a major role in stimulating the synthesis of immune effector molecules during innate immune responses. We have characterized ChAP-1, an AP-1-like protein in Crassostrea hongkongensis that is a member of the AP-1 family of proteins. ChAP-1 is composed of 290 amino acid residues with a Jun and bZIP domain at the N- and C-termini, respectively, a structure similar to that of known Ap-1 proteins. ChAP-1 mRNA is expressed in several tissues analyzed, with highest expression in the mantle. Expression of ChAP-1 increases in response to Vibrio alginolyticus, Salmo haemolyticus or Salmo cerevisiae infection and, despite the location of GFP-tagged full-length ChAP-1 protein in the cytoplasm, ChAP-1 activates the transcription of an L8G5-luc reporter gene, and its over-expression can also activate the AP-1-Luc reporter gene in HEK293T cells.
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    • "We were interested to determine whether this protein existed and how it bound to the cell membrane, because studies have shown that signal peptides help the TLR protein to bind to the cell membrane. LRR domains fold into a horseshoe (or arc) shape with a parallel β-sheet on the concave face with various secondary structures, and they are involved in ligand binding (Miggin et al., 2006). "
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    ABSTRACT: Alternative splicing is a cellular mechanism in eukaryotes that results in considerable diversity of gene products. It plays an important role in several diseases and cellular signal regulation. Heat stress is a major factor that induces immunosuppression in pigs. Little is known about the correlation between alternative splicing and heat stress in pigs. Therefore, this study aimed to clone, sequence, and quantify the alternative splicing variant of toll-like receptor 4 (TLR4) in Bama miniature pigs (Sus scrofa domestica) following exposure to heat stress. The results showed that the second exon of TLR4 was spliced and 167 bp shorter in the alternative splicing variant, and the protein was putatively identified as a type of truncated membrane protein consisting of extramembrane, transmembrane, and intramembrane regions lacking a signal peptide. Further, it was not a non-classical secretory protein. Five potential reference genes were screened for their potential as reliable standards to quantify the expression of TLR4 alternative spliced variants by qRT-PCR. The stability of these reference genes was ranked using the geNorm and NormFinder programs, and ribosomal protein L4 (RPL4) and TATA box-binding protein (TBP) were found to be the two genes showing the most stable expression in the in vitro cultured peripheral blood mononuclear cells (PBMCs) during heat shock. The mRNA level of the TLR4 gene (both classical and spliced) in stressed pigs increased significantly (p < 0.05). Further, the expression levels of the alternative spliced variant of TLR4 (TLR4-ASV) showed a two- to threefold increase in heat-stressed PBMCs as compared to control pigs. The results of the present study suggested that heat shock might modulate the host immune response by regulating the expressions of TLR4 and its alternative splicing variant.
    Journal of Integrative Agriculture 08/2013; 13(11):2479–2487. DOI:10.1016/S2095-3119(13)60574-2 · 0.63 Impact Factor
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    • "MyD88-independent pathways induce activation of IRF3 and expression of interferon-β. TIR-domain containing adaptors such as TIRAP, TRIF and TRAM regulate TLR-mediated signaling pathways by providing specificity for individual TLR signaling cascades [28] [29] [30] [31] [32] [33]. "
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