Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6

H Häcker, V Redecke, B Blagoev, I Kratchmarova… - Nature, 2006 - nature.com
H Häcker, V Redecke, B Blagoev, I Kratchmarova, LC Hsu, GG Wang, MP Kamps, E Raz…
Nature, 2006nature.com
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 1. TLRs activate downstream effectors through adaptors that
contain Toll/interleukin-1 receptor (TIR) domains 2, 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 …
Abstract
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 1. TLRs activate downstream effectors through adaptors that contain Toll/interleukin-1 receptor (TIR) domains 2, 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-β) 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.
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