Article: article from journal or magazin.
MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression.
Publication types: Journal Article
MyD88 is an adapter protein that is involved in Toll-like receptor (TLR)- and interleukin-1 receptor (IL-1R)-induced activation of nuclear factor-kappaB (NF-kappaB) 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, MyD88(S), which specifically prevents the recruitment of IRAK-4 into the IL-1R complex and thus inhibits IRAK-4-mediated IRAK-1 phosphorylation. MyD88(S) is not able to activate NF-kappaB, and in contrast functions as a dominant negative inhibitor of TLR/IL-1R-induced NF-kappaB activation. Unexpectedly, we here demonstrate that MyD88(S) still allows JNK phosphorylation and activator protein (AP)-1-dependent reporter gene induction upon overexpression in HEK293T cells. These observations indicate that NF-kappaB 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-kappaB- but not AP-1-dependent gene expression implies an important role for alternative splicing in the fine-tuning of TLR/IL-1R responses.
Adaptor Proteins, Signal Transducing, Antigens, Differentiation/physiology, Cell Line, Humans, Interleukin-1/pharmacology, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinases/metabolism, Myeloid Differentiation Factor 88, NF-kappa B/antagonists &, inhibitors, NF-kappa B/metabolism, Phosphorylation, Protein Isoforms/physiology, Protein Splicing, Receptors, Immunologic/physiology, Signal Transduction, Transcription Factor AP-1/metabolism
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