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.
Tseng
Ping-Hui
PH
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, USA.
Matsuzawa
Atsushi
A
Zhang
Weizhou
W
Mino
Takashi
T
Vignali
Dario A A
DA
Karin
Michael
M
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D054875:Ubiquitination
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D018836:Inflammation Mediators; D051034:Inhibitor of Apoptosis Proteins; D007370:Interferon Type I; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D053594:Myeloid Differentiation Factor 88; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse