Myeloid differentiation factor 88 (MyD88) plays a crucial role in the signaling pathways triggered by interleukin (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 Toll/IL-1 receptor (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 glutathione S-transferase-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-kappaB. 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.

Loiarro, M., Sette, C., Gallo, G., Fantò, N., Mastroianni, D., Carminati, P., et al. (2005). Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits IL-1-dependent activation of NF-kB. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 280, 15809-15814 [10.1074/jbc.C400613200].

Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits IL-1-dependent activation of NF-kB.

SETTE, CLAUDIO;
2005-01-01

Abstract

Myeloid differentiation factor 88 (MyD88) plays a crucial role in the signaling pathways triggered by interleukin (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 Toll/IL-1 receptor (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 glutathione S-transferase-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-kappaB. 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.
Pubblicato
Rilevanza internazionale
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Sì, ma tipo non specificato
Settore BIO/16
English
Con Impact Factor ISI
Loiarro, M., Sette, C., Gallo, G., Fantò, N., Mastroianni, D., Carminati, P., et al. (2005). Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits IL-1-dependent activation of NF-kB. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 280, 15809-15814 [10.1074/jbc.C400613200].
Loiarro, M; Sette, C; Gallo, G; Fantò, N; Mastroianni, D; Carminati, P; Ruggiero, V
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/39049
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