Viral Inhibitory Peptide of TLR4, a Peptide Derived from Vaccinia Protein A46, Specifically Inhibits TLR4 by Directly Targeting MyD88 Adaptor-Like and TRIF-Related Adaptor Molecule
Citation:
Lysakova-Devine, T., Keogh, B., Harrington, B., Nagpal, K., Halle, A., Golenbock, D.T., Monie, T. & Bowie, A.G., Viral Inhibitory Peptide of TLR4, a Peptide Derived from Vaccinia Protein A46, Specifically Inhibits TLR4 by Directly Targeting MyD88 Adaptor-Like and TRIF-Related Adaptor Molecule, The Journal of Immunology, 185, 2010, 4261 - 4271Download Item:
Abstract:
TLRs are critical pattern recognition receptors, which recognize bacterial and viral
pathogen associated molecular patterns leading to innate and adaptive immune
responses. TLRs signal via homotypic interactions between their cytoplasmic Toll-IL-
1 receptor (TIR) domains and TIR domain-containing adaptor proteins. Over the
course of evolution viruses have developed various immune evasion strategies, one of
which involves inhibiting TLR signaling pathways in order to avoid immune
detection. Thus, vaccinia virus (VACV) encodes the A46 protein, which binds to
multiple TIR-domain containing proteins, ultimately preventing TLRs from signaling.
We have identified an 11-amino acid long peptide from A46 (termed VIPER), which
when fused to a cell-penetrating delivery sequence potently inhibits TLR4-mediated
responses. VIPER was TLR4-specific, being inert towards other TLR pathways, and
was active in murine and human cells and in vivo, where it inhibited LPS-induced IL-
12p40 secretion. VIPER also prevented TLR4-mediated MAPK and transcription
factor activation, suggesting it acted close to the TLR4 complex. Indeed, VIPER
directly interacted with the TLR4 adaptor proteins Mal and TRAM. Viral proteins
target host proteins using evolutionary optimized binding surfaces. Thus VIPER
possibly represents a surface domain of A46 that specifically inhibits TLR4 by
masking critical binding sites on Mal and TRAM. Apart from its potential therapeutic
and experimental use in suppressing TLR4 function, identification of VIPER's
specific binding sites on TRAM and Mal may reveal novel therapeutic target sites.
Overall, we demonstrate for the first time disruption of a specific TLR signaling
pathway by a short virally-derived peptide.
Sponsor
Grant Number
Science Foundation Ireland (SFI)
R01GM54060
Author's Homepage:
http://people.tcd.ie/agbowieDescription:
PUBLISHED
Author: BOWIE, ANDREW
Type of material:
Journal ArticleCollections
Series/Report no:
The Journal of Immunology185
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Full text availableKeywords:
TLR4Subject (TCD):
Immunology, Inflammation & InfectionDOI:
http://dx.doi.org/10.4049/jimmunol.1002013Metadata
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