Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines.
Balanced production of type I interferons and proinflammatory cytokines after engagement of Toll-like receptors (TLRs), which signal through adaptors containing a Toll-interleukin 1 receptor (TIR) domain, such as MyD88 and TRIF, has been proposed to control the pathogenesis of autoimmune disease and tumor responses to inflammation. Here we show that ... TRAF3, a ubiquitin ligase that interacts with both MyD88 and TRIF, regulated the production of interferon and proinflammatory cytokines in different ways. Degradative ubiquitination of TRAF3 during MyD88-dependent TLR signaling was essential for the activation of mitogen-activated protein kinases (MAPKs) and production of inflammatory cytokines. In contrast, TRIF-dependent signaling triggered noncanonical TRAF3 self-ubiquitination that activated the interferon response. Inhibition of degradative ubiquitination of TRAF3 prevented the expression of all proinflammatory cytokines without affecting the interferon response.
Mesh Terms:
Adaptor Proteins, Vesicular Transport, Animals, Cell Line, Cytokines, Gene Expression Regulation, Immunoblotting, Inflammation Mediators, Inhibitor of Apoptosis Proteins, Interferon Type I, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinases, Myeloid Differentiation Factor 88, Phosphorylation, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 3, TNF Receptor-Associated Factor 6, Toll-Like Receptor 4, Ubiquitination
Adaptor Proteins, Vesicular Transport, Animals, Cell Line, Cytokines, Gene Expression Regulation, Immunoblotting, Inflammation Mediators, Inhibitor of Apoptosis Proteins, Interferon Type I, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinases, Myeloid Differentiation Factor 88, Phosphorylation, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 3, TNF Receptor-Associated Factor 6, Toll-Like Receptor 4, Ubiquitination
Nat. Immunol.
Date: Jan. 01, 2010
PubMed ID: 19898473
View in: Pubmed Google Scholar
Download Curated Data For This Publication
124760
Switch View:
- Interactions 23
- PTM Genes 2