Functional Diversity and Regulation of Different Interleukin-1 Receptor-Associated Kinase (IRAK) Family Members  Sophie Janssens, Rudi Beyaert  Molecular Cell  Volume 11, Issue 2, Pages 293-302 (February 2003) DOI: 10.1016/S1097-2765(03)00053-4

Figure 1 Schematic Representation of TLR/IL-1R Signaling IRAKs are essential signaling intermediates in the TLR/IL-1R pathway to both IKK and MAPKs activation. These two pathways are central to the activation of several transcription factors, including NF-κB and AP-1, which contribute to the establishment of an immune response (for a detailed description of these pathways, see the legend of Figure 3). Molecular Cell 2003 11, 293-302DOI: (10.1016/S1097-2765(03)00053-4)

Figure 2 Sequence Alignment and Functional Domains of the Four Human IRAK Homologs and Drosophila Pelle Sequences used in the alignment are from human IRAK-1 (NM_001569), human IRAK-2 (NM_001570), human IRAK-M (NM_007199), human IRAK-4 (NM_016123), and Drosophila pelle (L08476). The lysine in the ATP binding pocket (K239 for IRAK-1) and the catalytic site in protein kinase subdomain VIb (D340 for IRAK-1) are indicated by an asterisk. Molecular Cell 2003 11, 293-302DOI: (10.1016/S1097-2765(03)00053-4)

Figure 3 Overview of IL-1R-Mediated Signaling to NF-κB and JNK/p38 Signaling pathways are numbered and discussed step by step. (1) Ligand binding to IL-1R complex triggers the recruitment of MyD88 via a homophilic TIR-TIR interaction. MyD88 in its turn brings IRAK-4 into the receptor complex. In addition, preformed Tollip/IRAK-1 complexes are recruited to the receptor, which allows IRAK-1 to bind MyD88 via its DD. In this way, IRAK-1 and IRAK-4 come in close proximity, which allows IRAK-4 to phosphorylate IRAK-1 on critical residues that are necessary to trigger IRAK-1. TRAF6 is also recruited transiently to the receptor complex, via interaction with phosphorylated IRAK-1. (2) Phosphorylated IRAK-1 and TRAF6 dissociate from the receptor and interact at the membrane with a preformed complex consisting of TAK1, TAB1, and TAB2. This interaction induces phosphorylation of TAB2 and TAK1, which then translocate together with TRAF6 and TAB1 to the cytosol. IRAK-1 stays at the membrane, where it gets degraded, presumably via a ubiquitin-dependent mechanism. (3) In the cytosol, the multimeric protein complex composed of TRAF6, TAK1, TAB1, and TAB2 further associates with the ubiquitin ligases Ubc13 and Uev1A. This leads to ubiquitination of TRAF6, which is essential for triggering TAK1 kinase activity. (4) Activated TAK1 phosphorylates both the IKK complex (composed of the catalytic subunits IKK-α and IKK-β, as well as the regulatory subunit IKK-γ), as well as specific MKKs. IKKs phosphorylate the NF-κB inhibitor IκB, leading to its ubiquitination and subsequent degradation by the proteasome. This allows NF-κB to translocate to the nucleus and bind to specific promotor sequences. Activated MKKs phosphorylate and activate members of the JNK/p38 MAPK family. These also translocate to the nucleus where they can phosphorylate several transcription factors of the basic leucine zipper (bZIP) family, like c-Jun and c-Fos. Molecular Cell 2003 11, 293-302DOI: (10.1016/S1097-2765(03)00053-4)

Figure 4 Negative Regulation of TLR/IL-1R Signaling at the Level of IRAK (Left) TLR/IL-1R signaling pathways activated in the absence of endogenous negative regulators. For description, see Figure 3. To include IRAK-2 in the picture, signaling pathways initiated by TLR4 are shown. (Middle) MyD88S is an alternative splice variant of MyD88, induced by proinflammatory stimuli such as LPS or TNF. MyD88S competes with MyD88L for binding at the receptor, does not interfere with IRAK-1 recruitment, but no longer binds IRAK-4, preventing IRAK-1 phosphorylation. In this way, MyD88S acts as dominant-negative inhibitor of TLR/IL-1R-induced NF-κB activation. (Right) Another negative regulator of TLR/IL-1R-mediated signaling is IRAK-M. IRAK-M does not prevent IRAK-1 or IRAK-4 recruitment to the receptor complex, but inhibits IRAK-1 dissociation from the receptor complex after its activation and therefore blocks LPS-induced IRAK-1-TRAF6 interaction and NF-κB activation. In contrast to the other IRAKs, IRAK-M expression levels are tightly regulated and can be induced by treatment with LPS in monocytes. Molecular Cell 2003 11, 293-302DOI: (10.1016/S1097-2765(03)00053-4)