Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines.

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.

• Authors: Ping-Hui Tseng, Atsushi Matsuzawa, Weizhou Zhang, Takashi Mino, Dario A A Vignali, Michael Karin
• Journal: Nature immunology (Nat Immunol) Vol. 11 Issue 1 Pg. 70-5 (Jan 2010) ISSN: 1529-2916 [Electronic] United States
• PMID: 19898473 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Vesicular Transport
• Cytokines
• Inflammation Mediators
• Inhibitor of Apoptosis Proteins
• Interferon Type I
• Lipopolysaccharides
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• TICAM-1 protein, mouse
• TNF Receptor-Associated Factor 3
• TNF Receptor-Associated Factor 6
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Mitogen-Activated Protein Kinases

Topics

• Adaptor Proteins, Vesicular Transport (genetics, metabolism)
• Animals
• Cell Line
• Cytokines (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Immunoblotting
• Inflammation Mediators (metabolism)
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Interferon Type I (metabolism)
• Lipopolysaccharides (pharmacology)
• Macrophages (cytology, drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinases (metabolism)
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Phosphorylation
• Protein Binding
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• TNF Receptor-Associated Factor 3 (genetics, metabolism)
• TNF Receptor-Associated Factor 6 (genetics, metabolism)
• Toll-Like Receptor 4 (metabolism)
• Ubiquitination