Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88.
MyD88 is an adaptor protein that is involved in interleukin-1 receptor (IL-1R)- and Toll-like receptor (TLR)-induced activation of NF-kappaB. It is composed of a C-terminal Toll/IL-1R homology (TIR) domain and an N-terminal death domain (DD), which mediate the interaction of MyD88 with the IL-1R/TLR and the IL-1R-associated kinase (IRAK), respectively. The interaction of MyD88 with IRAK triggers IRAK phosphorylation, which is essential for its activation and downstream signaling ability. Both domains of MyD88 are separated by a small intermediate domain (ID) of unknown function. Here, we report the identification of a splice variant of MyD88, termed MyD88(S), which encodes for a protein lacking the ID. MyD88(S) is mainly expressed in the spleen and can be induced in monocytes upon LPS treatment. Although MyD88(S) still binds the IL-1R and IRAK, it is defective in its ability to induce IRAK phosphorylation and NF-kappaB activation. In contrast, MyD88(S) behaves as a dominant-negative inhibitor of IL-1- and LPS-, but not TNF-induced, NF-kappaB activation. These results implicate the ID of MyD88 in the phosphorylation of IRAK. Moreover, the regulated expression and antagonistic activity of MyD88(S) suggest an important role for alternative splicing of MyD88 in the regulation of the cellular response to IL-1 and LPS.
Janssens
Sophie
S
Department of Molecular Biology, Unit of Molecular Signal Transduction in Inflammation, Gent University - VIB, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium.
Burns
Kim
K
Tschopp
Jurg
J
Beyaert
Rudi
R
D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007375:Interleukin-1; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases