The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease
| Autor: | Elisabeth Kremmer, Derek L. Clouthier, Tania H. Watts, Achire N. Mbanwi, Maria I. Edilova, Ali A. Abdul-Sater |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides TRAF1 Gene Lipopolysaccharide medicine.medical_treatment Immunology TRAF1 Inflammation Biology Polymorphism Single Nucleotide Monocytes Proinflammatory cytokine Arthritis Rheumatoid 03 medical and health sciences chemistry.chemical_compound Mice medicine Immunology and Allergy Animals Humans Genetic Predisposition to Disease RNA Small Interfering Mice Knockout Toll-like receptor Toll-Like Receptors TNF Receptor-Associated Factor 1 Cell biology Mice Inbred C57BL 030104 developmental biology Cytokine HEK293 Cells chemistry Leukocytes Mononuclear Cytokines Tumor necrosis factor alpha medicine.symptom Inflammation Mediators Signal Transduction |
| Zdroj: | Nature immunology. 18(1) |
| ISSN: | 1529-2916 |
| Popis: | TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1-/- mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP. |
| Databáze: | OpenAIRE |
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