Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling
Resource
Inflamm. Bowel Dis., 18(5), 877-888
Journal
Inflammatory Bowel Diseases
Pages
877-888
Date Issued
2012
Date
2012
Author(s)
Abstract
Background: Toll-like receptors (TLRs) are expressed by a variety of cells, including intestinal epithelia. However, the full spectrum of regulators modulating innate responses via TLRs has not been delineated. Tribbles (Trib) have been identified as a highly conserved family of kinase-like proteins. We sought to clarify the role of Trib2 in the TLR signaling pathway. Methods: Trib2 mRNA and protein levels were analyzed by quantitative polymerase chain reaction (PCR) and western blot, respectively. Immunohistochemical staining was used to determine the expression of Trib2 in human tissue. Involvement of Trib2 in nuclear factor kappa B (NF-?B) pathways was assessed in epithelial cells by NF-?B reporter assay. Proteins that interacted with Trib2 were identified by mass spectrometry and confirmed by immunoprecipitation. The domain essential for Trib2 function was mapped using truncated constructs. Results: Trib2 expression is decreased in active inflamed tissue from patients with inflammatory bowel disease (IBD). Trib2 is expressed in human and mouse colonic epithelium as well as immune cells, and its expression in epithelium is inducible in a ligand-dependent manner by TLR5 ligand stimulation. Trib2 inhibits TLR5-mediated activation of NF-?B downstream of TRAF6. Trib2 selectively modulates mitogen-activated protein kinase (MAPK) pathways p38 and Jun N-terminal kinase (JNK) but not p44/p42 (ERK1/2). NF-?B2 (p100) was identified as a Trib2 binding partner in regulating the TLR5 signaling pathway that leads to inhibition of NF-?B activity. Residues 158177 in the Trib2 kinase-like domain are required for Trib2 function. Conclusions: These observations indicate that Trib2 is a novel regulator in the TLR5 signaling pathway and altered expression of Trib2 may play a role in IBD. (Inflamm Bowel Dis 2012;)
Subjects
Tribbles 2
Toll-like receptor
IBD
nuclear factor kappa B
MAPK
NF-?B2
SDGs
Other Subjects
complementary DNA; immunoglobulin enhancer binding protein; luciferase; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase p38; protein kinase; RNA; small interfering RNA; toll like receptor; toll like receptor 5; Tribbles 2 protein; tumor necrosis factor receptor associated factor 6; unclassified drug; adaptive immunity; article; cell strain HEK293; controlled study; enteritis; enzyme activity; enzyme assay; gene expression; human; human cell; human tissue; immune system; immunohistochemistry; inflammation; innate immunity; mass spectrometry; priority journal; protein domain; protein expression; protein protein interaction; real time polymerase chain reaction; reverse transcription polymerase chain reaction; signal transduction; Animals; Blotting, Western; Cells, Cultured; Gene Expression Regulation; Humans; Immunoenzyme Techniques; Immunoprecipitation; Inflammatory Bowel Diseases; Intracellular Signaling Peptides and Proteins; Luciferases; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; NF-kappa B p52 Subunit; Phosphorylation; Protein-Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Toll-Like Receptor 5
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