The MyD88 gene was originally described as one of several myeloid differentiation primary response genes that are induced in murine M1 myeloblastic leukemia cells upon stimulation with IL-6. It is an exclusively cytosolic protein that functions as a unique adaptor for members of the type I interleukin-1 receptor (IL-1R)/Toll like receptor (TLR) family. The MyD88 protein has a modular structure. At its N-terminus, it has a “death domain” (DD) similar to the cytoplasmic signaling domains found in many members of the tumor necrosis factor (TNF) receptor superfamily. Its C-terminal domain is conserved in all members of the TLR/IL-1R super family and is, therefore, termed the “Toll/IL-1R” (TIR) domain. Both domains are required for MyD88 homodimerization and are separated by a short intermediate domain (ID) of unknown function. The TIR domain of MyD88 forms a homophilic interaction with the TIR domain of IL-1R and IL-1 Receptor accessory protein (IL-IRacP), IL-18R, and several TLRs, whereas the DD binds with the DD of both IL-1 receptor associated kinase (IRAK) and IRAK-2. Interaction with MyD88 triggers IRAK phosphorylation. Phosphorylated IRAK leaves the receptor complex and associates with TNF receptor-associated factor 6 (TRAF 6), which forms a molecular link to activation of NF-κB and c-jun N-terminal kinase (JNK). Targeted disruption of the MyD88 gene showed unamnbiguously the importance of MyD88 in IL-1, IL-18 and TLR (including LPS) signaling pathways. All IL-1 and IL-18 responses (including T-cell proliferation and induction of cytokines and acute phase proteins) were abrogated in MyD88−/− cells and no NF-κB or JNK activity was observed. MyD88−/− cells were resistant to LPS-induced endotoxic shock, but still showed delayed NF-κB translocation to the nucleus, which suggests redundancy at the level of MyD88 in the LPS-pathway.
MyD88 mRNA expression has been found to be constitutively expressed in many adult human tissues as a 2.6 kb mRNA species. In the present invention, we describe the identification, characterization and uses of a splice variant of MyD88, termed MyD88S, which encodes for a protein lacking the ID. We have disclosed earlier the occurrence of an unknown splice variant of MyD88, lacking part of the TIR domain, that can inhibit IL1-induced NF-κB activation (Janssens S. and Beyaert R. (2000) Scandinavian J. of Immunology, 51 (Suppl. 1), 1.
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