MyD88S, a splice variant of MyD88, differentially modulates NF‐κB‐ and AP‐1‐dependent gene expression

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Abstract
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.