HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 16, 15809-15814, April 22, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/16/15809    most recent C400613200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Loiarro, M. Articles by Ruggiero, V. Search for Related Content PubMed PubMed Citation Articles by Loiarro, M. Articles by Ruggiero, V. Social Bookmarking                      What's this?

Peptide-mediated Interference of TIR Domain Dimerization in MyD88 Inhibits Interleukin-1-dependent Activation of NF-B^*

Maria Loiarro, Claudio Sette, Grazia Gallo, Andrea Ciacci, Nicola Fantò, Domenico Mastroianni¶, Paolo Carminati, and Vito Ruggiero||

From the Department of Public Health and Cell Biology, University of Rome "Tor Vergata," 00173 Rome, Italy, the Sigma-Tau Industrie Farmaceutiche Riunite S.p.A, 00040 Pomezia, Italy, and ^¶Tecnogen SCpA, 81015 Piana di Monte Verna (CE), Italy

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-B. 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.

Received for publication, December 27, 2004 , and in revised form, March 4, 2005.

^* This work was supported by a Research Contract (Conto Terzi) from Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. (to C. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A, Dept. of Immunology (Bldg. LABIO), Via Pontina km 30.400, 00040 Pomezia (RM), Italy. Tel.: 39-6-9139-4277; Fax: 39-6-9139-3988; E-mail: vito.ruggiero{at}Sigma-Tau.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Nyman, P. Stenmark, S. Flodin, I. Johansson, M. Hammarstrom, and P. Nordlund The Crystal Structure of the Human Toll-like Receptor 10 Cytoplasmic Domain Reveals a Putative Signaling Dimer J. Biol. Chem., May 2, 2008; 283(18): 11861 - 11865. [Abstract] [Full Text] [PDF]

				N. Funderburg, M. M. Lederman, Z. Feng, M. G. Drage, J. Jadlowsky, C. V. Harding, A. Weinberg, and S. F. Sieg Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2 PNAS, November 20, 2007; 104(47): 18631 - 18635. [Abstract] [Full Text] [PDF]

				M. Loiarro, F. Capolunghi, N. Fanto, G. Gallo, S. Campo, B. Arseni, R. Carsetti, P. Carminati, R. De Santis, V. Ruggiero, et al. Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound J. Leukoc. Biol., October 1, 2007; 82(4): 801 - 810. [Abstract] [Full Text] [PDF]

				D. Filipponi, R. M. Hobbs, S. Ottolenghi, P. Rossi, E. A. Jannini, P. P. Pandolfi, and S. Dolci Repression of kit Expression by Plzf in Germ Cells Mol. Cell. Biol., October 1, 2007; 27(19): 6770 - 6781. [Abstract] [Full Text] [PDF]

				H. F. Rosenberg Rational design of MyD88 inhibitors new pathways to inflammatory control: an interview with Dr. Claudio Sette J. Leukoc. Biol., October 1, 2007; 82(4): 811 - 812. [Full Text] [PDF]

				J. Fan, Y. Li, R. M. Levy, J. J. Fan, D. J. Hackam, Y. Vodovotz, H. Yang, K. J. Tracey, T. R. Billiar, and M. A. Wilson Hemorrhagic Shock Induces NAD(P)H Oxidase Activation in Neutrophils: Role of HMGB1-TLR4 Signaling J. Immunol., May 15, 2007; 178(10): 6573 - 6580. [Abstract] [Full Text] [PDF]

				T. Uto, X. Wang, K. Sato, M. Haraguchi, T. Akagi, M. Akashi, and M. Baba Targeting of Antigen to Dendritic Cells with Poly({gamma}-Glutamic Acid) Nanoparticles Induces Antigen-Specific Humoral and Cellular Immunity J. Immunol., March 1, 2007; 178(5): 2979 - 2986. [Abstract] [Full Text] [PDF]

				J. K. Gautam, Ashish, L. D. Comeau, J. K. Krueger, and M. F. Smith Jr. Structural and Functional Evidence for the Role of the TLR2 DD Loop in TLR1/TLR2 Heterodimerization and Signaling J. Biol. Chem., October 6, 2006; 281(40): 30132 - 30142. [Abstract] [Full Text] [PDF]

				M. V. Lasker and S. K. Nair Intracellular TLR Signaling: A Structural Perspective on Human Disease J. Immunol., July 1, 2006; 177(1): 11 - 16. [Abstract] [Full Text] [PDF]

				G. Canny, E. Cario, A. Lennartsson, U. Gullberg, C. Brennan, O. Levy, and S. P. Colgan Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein Am J Physiol Gastrointest Liver Physiol, March 1, 2006; 290(3): G557 - G567. [Abstract] [Full Text] [PDF]