ArticleThe Journal of biological chemistry2010
TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 39 citations in OpenAlex.
- Revealing the Mechanism of Buzhong Yiqi Tang in Ameliorating Autoimmune ThyroiditisCombinatorial chemistry & high throughput screening · 2026Article
- TLRs in Mycobacterial Pathogenesis: Black and White or Shades of Gray.Current microbiology · 2021Review
- Corticotropin-Releasing Hormone Receptor Alters the Tumor Development and Growth inInternational journal of molecular sciences · 2021Article
- Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury.Acta neuropathologica communications · 2020Article
- Host Immune Response and Novel Diagnostic Approach to NTM Infections.International journal of molecular sciences · 2020Review
- Differential expression of tumor-associated genes and altered gut microbiome with decreased Akkermansia muciniphila confer a tumor-preventive microenvironment in intestinal epithelial Pten-deficient mice.Biochimica et biophysica acta. Molecular basis of disease · 2018Article
- Colonic Inhibition of Phosphatase and Tensin Homolog Increases Colitogenic Bacteria, Causing Development of Colitis in Il10-/- Mice.Inflammatory bowel diseases · 2018Article
- Src family kinase tyrosine phosphorylates Toll-like receptor 4 to dissociate MyD88 and Mal/Tirap, suppressing LPS-induced inflammatory responses.Biochemical pharmacology · 2018Article
- Mycoplasma hyorhinis-Contaminated Cell Lines Activate Primary Innate Immune Cells via a Protease-Sensitive Factor.PloS one · 2015Article
- The TIR-domain containing adaptor TRAM is required for TLR7 mediated RANTES production.PloS one · 2014Article
- Toll-like receptor 3 in viral pathogenesis: friend or foe?Immunology · 2013Review
- PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2013Article
- Toll-like receptor 5 engagement induces interleukin-17C expression in intestinal epithelial cells.Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research · 2012Article
- Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice.American journal of physiology. Gastrointestinal and liver physiology · 2012Article
- TLR5, a novel and unidentified inflammatory mediator in rheumatoid arthritis that correlates with disease activity score and joint TNF-α levels.Journal of immunology (Baltimore, Md. : 1950) · 2012Article
- Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine.PloS one · 2012Article
- Deciphering the function of nucleic acid sensing TLRs one regulatory step at a time.Frontiers in bioscience (Landmark edition) · 2011Review
- Basic and translational understandings of microbial recognition by toll-like receptors in the intestine.Journal of neurogastroenterology and motility · 2011Article
- TRIF is a critical negative regulator of TLR agonist mediated activation of dendritic cells in vivo.PloS one · 2011Article
- TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells.The Journal of biological chemistry · 2010Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Proteolytic modification of pattern recognition receptors and their signaling adaptor molecules has recently emerged as an essential cellular event to regulate immune and inflammatory responses. Here we show that the TIR domain containing adaptor-inducing interferon-beta (TRIF), an adaptor molecule mediating TLR3 signaling and MyD88-independent signaling of TLR4, plays an inhibitory role in TLR5-elicited responses by inducing proteolytic degradation of TLR5. TRIF overexpression in human embryonic kidney (HEK293) and human colonic epithelial (NCM460) cells abolishes the cellular protein level of TLR5, whereas it does not alter TLR5 mRNA level. Thus, TRIF overexpression dramatically suppresses flagellin/TLR5-deriven NFkappaB activation in NCM460 cells. TRIF-induced TLR5 protein degradation is completely inhibited in the presence of pan-caspase inhibitor (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), whereas several specific inhibitors against cathepsin B, reactive oxygen species, or ubiquitin-mediated proteasome activity fail to suppress this degradation. These results indicate that TRIF-induced caspase activity causes TLR5 protein degradation. In addition, we identify that the C terminus of TRIF and extracellular domain of TLR5 are required for TRIF-induced TLR5 degradation. Furthermore, TRIF-induced proteolytic degradation is extended to TLR3, TLR6, TLR7, TLR8, TLR9, and TLR10, whereas the cellular level of TLR1, TLR2, and TLR4 is not affected by TRIF overexpression. These results suggest that, in addition to mediating TLR3- or TLR4-induced signaling as an adaptor molecule, TRIF can participate in proteolytic modification of certain members of TLRs to modulate the functionality of TLRs at post-translational level. Collectively, our findings propose a potential inhibitory role of TRIF at least in regulating host-microbial communication via TLR5 in colonic epithelial cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.