48 Nature Immunology, 2011TLR4 signaling activates the canonical IKK complex via MyD88-dependent and TRIF-dependent mechanisms. MyD88 assembles complexes that contain IRAK kinases together with TRAF6, TAB2, TAB3 and TAK1. TRIF can directly recruit TRAF6 and recruit TAB2, TAB3 and TAK1. The active NF-κB pathway subsequently induces expression of the alternative MyD88 splice product MyD88s, the kinase-inactive IRAK family member IRAK-M and the negative regulatory adaptor molecule SARM. These dominant-negative factors presumably affect the stability of the IKK-activating complexes.