The IL-1 receptor accessory protein is essential for PI 3-kinase recruitment and activation.

Interleukin-1 (IL-1) binds to its type I receptors (IL-1R), which in complex with IL-1R accessory protein (IL-1R AcP) induces various intracellular signaling events. We report here that IL-1 triggers the recruitment of phosphoinositide 3-kinase (PI 3-kinase) to a signaling complex and induces its lipid kinase activity in a biphasic manner. This IL-1-induced complex consists of IL-1R, IL-1R AcP, PI 3-kinase, and the IL-1-receptor-associated kinase (IRAK). Deletion of the C-terminus 27 amino acids of IL-1R AcP resulted in a mutant, CDelta27, that could not recruit PI 3-kinase to the signalsome nor stimulate PI3-kinase activity. Moreover, CDelta27 functioned as a dominant-negative mutant that inhibited IL-1-induced PI 3-kinase and NFkappaB activation. CDelta27, however, had no effect on IL-1-dependent activation of the Jun N-terminal kinase (JNK), indicating that distinct regions of IL-1R AcP mediate the activation of PI 3-kinase and JNK. Thus, our results identified a functional region in the IL-1R AcP required for the recruitment and activation of PI 3-kinase.

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