Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.
Toll-like receptors (TLRs) are activated by pathogen-associated molecular patterns to induce innate immune responses and production of pro-inflammatory cytokines, interferons and anti-inflammatory cytokines. TLRs activate downstream effectors through adaptors that contain Toll/interleukin-1 receptor (TIR) domains, but the mechanisms accounting for diversification of TLR effector functions are unclear. To dissect biochemically TLR signalling, we established a system for isolating signalling complexes assembled by dimerized adaptors. Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. Using myeloid cells from TRAF3- and TRAF6-deficient mice, we show that TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. In fact, TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production. Despite their structural similarity, the functions of TRAF3 and TRAF6 are largely distinct. TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response.
Häcker
Hans
H
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. Hans.Haecker@stjude.org
Redecke
Vanessa
V
Blagoev
Blagoy
B
Kratchmarova
Irina
I
Hsu
Li-Chung
LC
Wang
Gang G
GG
Kamps
Mark P
MP
Raz
Eyal
E
Wagner
Hermann
H
Häcker
Georg
G
Mann
Matthias
M
Karin
Michael
M
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007372:Interferons / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D007372:Interferons; D016753:Interleukin-10; D053594:Myeloid Differentiation Factor 88; D017346:Protein Serine-Threonine Kinases; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C498588:Tbk1 protein, mouse