Spatial and temporal organization of Interleukin-1 receptor and Toll-like receptor signalling

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Signalling through Interleukin 1 receptor (IL-1RI) and Toll-like receptors (TLRs) is pivotal for pathogen detection by the innate immune system. IL-1RI/TLR signalling is regulated by protein kinases of the Interleukin-1 receptor associated kinase (IRAK) family. We recently demonstrated the modification of IRAK1 with an unusual polyubiquitin chain that is linked via Lysine 63 (K63) of ubiquitin, which is key for the IL-1-dependent activation of the transcription factor nuclear factor κB (NFκB). Furthermore, we demonstrated the IL-1-stimulated degradation of IRAK1 by an unknown mechanism. Surprising recent discoveries suggest a novel regulatory role for IRAK1 degradation. IL-1RI/TLR-mediated signal transduction appears to be divided into an early IRAK1-dependent phase of (<1 h) and a late IRAK2-dependent phase (4-16 h). We postulate that the IRAK1 degradation is a key regulatory mechanism for the transition from the early to the late phase. To test this hypothesis we will identify and inhibit the machinery for IRAK1 degradation. The molecular mechanisms of the IRAK2-dependent signal transduction are completely unknown. We will identify interaction partners and potential kinase substrates of IRAK2. Since both IL-1RI and TLR4 are internalized upon ligand binding, we hypothesize that the IRAK1-dependent early phase signalling takes place at the plasma membrane, whereas the IRAK2-dependent signalling events are initiated in the late phase from an intracellular compartment. To test this hypothesis, we will analyse the intracellular localization and trafficking of IRAK1 and IRAK2.