MyD88 is an adapter protein that is involved in Toll-like receptor (TLR)- and interleukin-1 receptor (IL-1R)-induced activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). By directly binding IL-1R-associated kinase (IRAK)-1 and IRAK-4, MyD88 serves as a bridging protein, enabling IRAK-4-induced IRAK-1 phosphorylation. We previously identified a lipopolysaccharide-inducible splice variant of MyD88, MyD88S, which specifically prevents the recruitment of IRAK-4 into the IL-1R complex and thus inhibits IRAK-4-mediated IRAK-1 phosphorylation. MyD88S is not able to activate NF-κB, and in contrast functions as a dominant negative inhibitor of TLR/IL-1R-induced NF-κB activation. Unexpectedly, we here demonstrate that MyD88S still allows JNK phosphorylation and activator protein (AP)-1-dependent reporter gene induction upon overexpression in HEK293T cells. These observations indicate that NF-κB and JNK activation pathways can already diverge at the level of MyD88. Moreover, the regulated expression of a MyD88 splice variant which specifically interferes with NF-κB- but not AP-1-dependent gene expression implies an important role for alternative splicing in the fine-tuning of TLR/IL-1R responses.
