Figure 8.

Scheme showing the role of kinase and scaffolding activity of IRAK4 in IL-1 signaling. In the unstimulated complex or the MyD88 interaction–incompetent R12C IRAK4 variant (left), no myddosome is formed, leading to complete loss of IL-1 signaling. In the active complex (center) a myddosome is formed with weak association of IRAK4 and MyD88 and strong association of IRAK4 and IRAK1 that potentiates robust ubiquitination and phosphorylation of IRAK1 and strong downstream signaling from the IL-1 receptor. In the IRAK4 kinase–inhibited complex (right), a myddosome is formed where IRAK4 is strongly associated with MyD88 but weakly associated with IRAK1, which reduces ubiquitination of IRAK1 and decreases IL-1–induced signaling and cytokine production.