Regulation of interleukin-1-and lipopolysaccharide-induced NF-κB activation by alternative splicing of MyD88

MyD88 is an adaptor protein that is involved in interleukin-1 receptor (IL-1 R)- and Toll-like receptor (TLR)-induced activation of NF-kappaB [1-3]. It is composed of a C-terminal Toll/IL-IR homology (TIR) domain and an N-terminal death domain (DD), which mediate the interaction of MyD88 with the IL-1R/TLR and the IL-1R-associated kinase (IRAK), respectively. The interaction of MyD88 with IRAK triggers IRAK phosphorylation, which is essential for its activation and downstream signaling ability [4, 5]. Both domains of MyD88 are separated by a small intermediate domain (ID) of unknown function. Here, we report the identification of a splice variant of MyD88, termed MyD88s, which encodes for a protein lacking the ID. MyD88s is mainly expressed in the spleen and can be induced in monocytes upon LIPS treatment. Although MyD88s still binds the IL-1R and IRAK, it is defective in its ability to induce IRAK phosphorylation and NF-kappaB activation. In contrast, MyD88s behaves as a dominant-negative inhibitor of IL-1- and LPS-, but not TNF-induced, NF-kappaB activation. These results implicate the ID of MyD88 in the phosphorylation of IRAK. Moreover, the regulated expression and antagonistic activity of MyD88s suggest an important role for alternative splicing of MyD88 in the regulation of the cellular response to IL-1 and LPS.