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Papers In Press, published online ahead of print March 8, 2005
Department of Immunology, Sigma-Tau S.p.A., Pomezia (RM)
Corresponding Author: vito.ruggiero{at}sigma-tau.it
MyD88 plays a crucial role in the signaling pathways triggered by IL-1 and Toll-like receptors in several steps of innate host defense. A crucial event in this signaling pathway is represented by dimerization of MyD88, which allows the recruitment of downstream kinases like IRAK-1 and IRAK-4. Herein, we have investigated the function of the TIR domain in MyD88 homodimerization in cell-free and in vitro experimental settings by using epta-peptides that mimic the BB-loop region of the conserved TIR domain of different proteins. By using a pull-down assay with purified GST-MyD88 TIR or co-immunoprecipitation experiments, we found that epta-peptides derived from the TIR domain of MyD88 and IL-18R are the most effective in inhibiting homodimerization with either the isolated TIR or full-length MyD88. Moreover, we demonstrated that a cell permeable analog of MyD88 epta-peptide inhibits homodimerization of MyD88 TIR domains in an in vitro cell system and significantly reduces IL-1 signaling, as assayed by activation of the downstream transcription factor NF-kB. Our results indicate that the BB-loop in TIR domain of MyD88 is a good target for specific inhibition of MyD88-mediated signaling in vivo.
J. Biol. Chem, 10.1074/jbc.C400613200
Submitted on December 27, 2004
Revised on March 4, 2005
Accepted on March 8, 2005
Peptide-mediated interference of tir domain dimerization in MyD88 inhibits IL-1-dependent activation of NF-kB
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