MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression.
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.
Janssens
Sophie
S
Department of Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Ghent University - VIB, Technologiepark 927, B-9052, Ghent, Belgium.
Burns
Kim
K
Vercammen
Elisabeth
E
Tschopp
Jurg
J
Beyaert
Rudi
R
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000502:physiology; D019154:Protein Splicing; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007375:Interleukin-1; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D020033:Protein Isoforms; D011971:Receptors, Immunologic; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases