Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism*
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Animals
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Cell Line
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Cytokines / genetics
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Cytokines / metabolism*
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Gene Expression Regulation / drug effects
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Immunoblotting
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Inflammation Mediators / metabolism
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Interferon Type I / metabolism*
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Lipopolysaccharides / pharmacology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinases / metabolism
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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Phosphorylation
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Protein Binding
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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TNF Receptor-Associated Factor 3 / genetics
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TNF Receptor-Associated Factor 3 / metabolism*
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Toll-Like Receptor 4 / metabolism
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Ubiquitination
Substances
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Adaptor Proteins, Vesicular Transport
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Cytokines
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Inflammation Mediators
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Inhibitor of Apoptosis Proteins
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Interferon Type I
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Lipopolysaccharides
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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TICAM-1 protein, mouse
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TNF Receptor-Associated Factor 3
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TNF Receptor-Associated Factor 6
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Mitogen-Activated Protein Kinases