Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain

Interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate transc ription factors AP-1 and NF-kappa B through activation of the MAP kinases J NK and p38 and the I kappa B kinase (IKK), respectively. The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpr essed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellu lar stimulation. By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of the immunophilin FKBP12, we demonstrate that their e ffector domains are composed of their amino-terminal Zn and RING fingers. O ligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induct ion of TNF-alpha and IL-1 responsive genes. TNF-alpha also enhances the bin ding of native TRAF2 to MEKK1 and stimulates the kinase activity of the lat ter. Thus, TNF-alpha and IL-1 signaling is based on oligomerization of TRAF 2 and TRAF6 leading to activation of effector kinases.