Abstract
The interleukin-1 (IL-1) receptor-associated kinase (IRAK) is required for the IL-1-induced activation of nuclear factor kappaB and c-Jun N-terminal kinase. The goal of this study was to understand how IRAK activates the intermediate proteins TRAF6, TAK1, TAB1, and TAB2. When IRAK is phosphorylated in response to IL-1, it binds to the membrane where it forms a complex with TRAF6; TRAF6 then dissociates and translocates to the cytosol. The membrane-bound IRAK similarly mediates the IL-1-induced translocation of TAB2 from the membrane to the cytosol. Different regions of IRAK are required for the translocation of TAB2 and TRAF6, suggesting that IRAK mediates the translocation of each protein separately. The translocation of TAB2 and TRAF6 is needed to form a TRAF6-TAK1-TAB1-TAB2 complex in the cytosol and thus activate TAK1. Our results show that IRAK is required for the IL-1-induced phosphorylation of TAK1, TAB1, and TAB2. The phosphorylation of these three proteins correlates strongly with the activation of nuclear factor kappaB but is not necessary to activate c-Jun N-terminal kinase.
Highlights
The interleukin-1 (IL-1) receptor-associated kinase (IRAK) is required for the IL-1-induced activation of nuclear factor B and c-Jun N-terminal kinase
We found that different regions of IL-1 receptor-associated kinase (IRAK) are required for the translocation of TAB2 and tumor necrosis factor receptor-associated factor 6 (TRAF6), suggesting that IRAK mediates these two events separately
The domains of IRAK required for the IL-1-induced translocation of TRAF6 are the same as those necessary for the IL-1-induced phosphorylation of Transforming growth factor--activated kinase 1 (TAK1), TAB1, and TAB2 and activation of nuclear factor-B (NFB) [15] (Fig. 9), revealing a tight correlation between the translocation of TRAF6 and the activation of downstream signaling
Summary
The interleukin-1 (IL-1) receptor-associated kinase (IRAK) is required for the IL-1-induced activation of nuclear factor B and c-Jun N-terminal kinase. Our results show that IRAK is required for the IL-1-induced phosphorylation of TAK1, TAB1, and TAB2 The phosphorylation of these three proteins correlates strongly with the activation of nuclear factor B but is not necessary to activate c-Jun N-terminal kinase. TAB2 is membrane-bound in untreated cells but translocates to the cytosol upon stimulation with IL-1, where it functions as an adaptor, linking TRAF6 to TAK1 and TAB1, thereby activating TAK1 [19]. IRAK-K239A and IRAKdKD complemented all defects in IL-1-dependent signaling in mutant I1A cells, indicating that the kinase activity of IRAK is not required for these functions [14, 15]. IL-1-induced phosphorylation of IRAK is required to activate NFB but not JNK [15] Taken together, these results strongly suggest that the IL-1-induced signaling pathways leading to NFB and JNK activation diverge at or upstream of IRAK
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