Fig. 3. IRAK4 is the upstream kinase that transduces TLRs and IL-1R signals.

IL-1 receptor (IL-1R)-associated kinase 1 (IRAK1) and IRAK4 function is regulated by protein–protein interactions and by post-translational modifications that may be uniquely regulated in different cell types to fine-tune an immune response. IL-1R or Toll-like receptor (TLR; except for TLR3) engagement causes the recruitment of adaptor protein myeloid differentiation primary response 88 (MyD88) to the intracellular Toll/IL-1R receptor (TIR) domains to initiate the Myddosome assembly. MyD88 recruits IRAK4 via death domain interactions. IRAK4 is activated via autophosphorylation and is also K63-ubiquitylated (grey circles). Phosphorylated IRAK4 can activate IRAK1, which facilitates IRAK1–tumour necrosis factor receptor-associated factor 6 (TRAF6) complex formation. K48 ubiquitylation (blue circles) of IRAK1 is required for the activation of TGFβ-activated kinase 1-binding protein 1 (TAK1), and its binding to TAB1 and TAB2 to drive the formation of the inhibitor of NF-κB (IKK) complex and subsequent NF-κB inhibitor-α (IκBα) activation, which then leads to NF-κB, mitogen-activated protein kinase (MAPK) and interferon-regulatory factor (IRF) activation to induce the transcription of pro-inflammatory cytokines and cellular processes, such as proliferation and activation^61,62. The mechanism of IRF activation by MyD88 is less understood. Downstream of IRAK4 activation, TAK1 and IKKβ complex can mediate IRF5 phosphorylation, nuclear translocation and transcription in monocytes⁷⁴, but IRAK1 can also directly bind and phosphorylate IRF7 in plasmacytoid dendritic cells²⁶³. The mechanism of IRAK4 kinase activity-independent action is less understood but may involve K63-ubiquitylated signalling hubs and other novel molecular scaffolds⁹². AP-1, activator protein 1; CREB, cAMP response element-binding protein; P, phosphorus; TAB, TGFβ-activated kinase 1 binding protein; Ub, ubiquitin.