Interleukin-1 (IL-1)-induced TAK1-dependent versus MEKK3-dependent NFκB activation pathways bifurcate at IL-1 receptor-associated kinase modification

Interleukin-1 (IL-1) receptor-associated kinase (IRAK) is phosphorylated after it is recruited to the receptor, subsequently ubiquitinated, and eventually degraded upon IL-1 stimulation. Although a point mutation changing lysine 134 to arginine (K134R) in IRAK abolished IL-1-induced IRAK ubiquitination and degradation, mutations of serines and threonines adjacent to lysine 134 to alanines ((S/T)A (131-144)) reduced IL-1-induced IRAK phosphorylation and abolished IRAK ubiquitination. Through the study of these IRAK modification mutants, we uncovered two parallel IL-1-mediated signaling pathways for NF kappa B activation, TAKI-dependent and MEKK3-dependent, respectively. These two pathways bifurcate at the level of IRAK modification. The TAKI-dependent pathway leads to IKK alpha/beta phosphorylation and IKK beta activation, resulting in classical NF kappa B activation through I kappa B alpha phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway involves IKK gamma phosphorylation and IKK alpha activation, resulting in NF kappa B activation through I kappa B alpha phosphorylation and subsequent dissociation from NF kappa B but without I kappa B alpha degradation. These results provide significant insight to our further understanding of NF kappa B activation pathways.