Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits interleukin-1-dependent activation of NF-κB

Maria Loiarro, Claudio Sette, Grazia Gallo, Andrea Ciacci, Nicola Fantó, Domenico Mastroianni, Paolo Carminati, Vito Ruggiero

Research output: Contribution to journalArticle

131 Citations (Scopus)

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-κB. 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.

Original languageEnglish
Pages (from-to)15809-15814
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number16
DOIs
Publication statusPublished - Apr 22 2005

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Myeloid Differentiation Factor 88
Interleukin-1 Receptors
Dimerization
Interleukin-1
Chemical activation
Peptides
Interleukin-1 Receptor-Associated Kinases
Toll-Like Receptors
Interleukins
Glutathione Transferase
Immunoprecipitation
Assays
Transcription Factors
Phosphotransferases

ASJC Scopus subject areas

  • Biochemistry

Cite this

Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits interleukin-1-dependent activation of NF-κB. / Loiarro, Maria; Sette, Claudio; Gallo, Grazia; Ciacci, Andrea; Fantó, Nicola; Mastroianni, Domenico; Carminati, Paolo; Ruggiero, Vito.

In: Journal of Biological Chemistry, Vol. 280, No. 16, 22.04.2005, p. 15809-15814.

Research output: Contribution to journalArticle

Loiarro, M, Sette, C, Gallo, G, Ciacci, A, Fantó, N, Mastroianni, D, Carminati, P & Ruggiero, V 2005, 'Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits interleukin-1-dependent activation of NF-κB', Journal of Biological Chemistry, vol. 280, no. 16, pp. 15809-15814. https://doi.org/10.1074/jbc.C400613200
Loiarro, Maria ; Sette, Claudio ; Gallo, Grazia ; Ciacci, Andrea ; Fantó, Nicola ; Mastroianni, Domenico ; Carminati, Paolo ; Ruggiero, Vito. / Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits interleukin-1-dependent activation of NF-κB. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 16. pp. 15809-15814.
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