Article

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.

Full-text

Available from: Sinead M Miggin, Apr 21, 2015
2 Followers
 · 
124 Views
  • Source
    Pesquisa Veterinária Brasileira 01/2015; 35(1):1. · 0.44 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptor 7 (TLR7) plays a vital role in the immune response to ssRNA viruses such as human rhinovirus (HRV) and Influenza, against which there are currently no treatments or vaccines with long term efficacy available. Clearly, a more comprehensive understanding of the TLR7 signaling axis will contribute to its molecular targeting. TRIF related adaptor molecule (TRAM) plays a vital role in TLR4 signaling by recruiting TRIF to TLR4, followed by endosomal trafficking of the complex and initiation of IRF3 dependent type I interferon production as well as NF-κB dependent pro-inflammatory cytokine production. Towards understanding the molecular mechanisms that regulate TLR7 functionality, we found that TRAM-/- murine macrophages exhibited a transcriptional and translational impairment in TLR7 mediated RANTES, but not TNFα, production. Suppression of TRAM expression in human macrophages also resulted in an impairment in TLR7 mediated CCL5 and IFN-β, but not TNFα, gene induction. Furthermore, suppression of endogenous human TRAM expression in human macrophages significantly impaired RV16 induced CCL5 and IFNβ, but not TNFα gene induction. Additionally, TRAM-G2A dose-dependently inhibited TLR7 mediated activation of CCL5, IFNβ and IFNα reporter genes. TLR7-mediated phosphorylation and nuclear translocation of IRF3 was impaired in TRAM-/- cells. Finally, co-immunoprecipitation studies indicated that TRAM physically interacts with MyD88 upon TLR7 stimulation, but not under basal conditions. Our results clearly demonstrate that TRAM plays a, hitherto unappreciated, role in TLR7 signaling through a novel signaling axis containing, but not limited to, MyD88, TRAM and IRF3 towards the activation of anti-viral immunity.
    PLoS ONE 09/2014; 9(9):e107141. DOI:10.1371/journal.pone.0107141 · 3.53 Impact Factor