Recent investigations by our group (1,2) and several others (e.g. 3,4) have emphasized the central role of TRAF6 in signaling events mediated by IL-1 and pathogen-associated molecular patterns (PAMPS).  For example, when cells are stimulated by the proinflammatory cytokine interleukin-1 (IL-1), the IL-1 receptor (IL-1R) forms a complex with IL-1 receptor accessory protein (IL-1RAcP), and recruits the cytosolic myeloid differentiation protein (MyD88) and the serine/ threonine kinase, IL-1 receptor-associated kinase (IRAK)(Figure 1).  IRAK gets activated, auto-phosphorylated, and dissociates from the receptor signaling complex to interact with TRAF6.  TRAF6 then forms a complex with TAK1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, and two important adapter proteins, TAB1 and TAB2.  TAK1 was first reported as a regulator of MAP kinase signaling induced by TGF-b It was subsequently shown to be involved in BMP signaling in early Xenopus development and in Wnt signaling in Drosophila.  Activated TAK1 further stimulates MAP kinase cascades leading to JNK activation and NF-kB activation.  Similar signaling events also are utilized by the Toll-like receptor superfamily (TLRs), which respond to bacterial lipopolysaccharides (LPS) and other PAMPS.

Figure 1. Schematic representation of the IL-1 signaling pathway.

I intend to elucidate the molecular mechanisms involved in IL-1 signal transduction, in particular, the MyD88-IRAK interaction and the TRAF6-mediated activation of TAK1.  Both MyD88 and IRAK are upstream activators of TRAF6.  They interact with each other upon IL-1 stimulation via the so-called death domains in these proteins.  I am especially interested in the mechanism for the activation of IRAK kinase upon the formation of the complex and also how IRAK interacts with TRAF6.

Aim 1.  Structural studies of the MyD88-IRAK interaction.

Aim 2.  Structural studies of the IRAK/TRAF6 interaction.

Aim 3.  Structural studies of the TRAF6/TAK1 interaction.

Aim 4.  Structural studies of the TAB1/TAK1 interaction.

Aim 5.  Structural studies of the TRAF6/TAK1/TAB1/TAB2 interaction.