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The Epithelial αvβ3-Integrin Boosts the MYD88-Dependent TLR2 Signaling in Response to Viral and Bacterial Components
- Source :
- PLoS Pathogens, PLoS Pathogens, Vol 10, Iss 11, p e1004477 (2014)
- Publication Year :
- 2014
- Publisher :
- Public Library of Science, 2014.
-
Abstract
- TLR2 is a cell surface receptor which elicits an immediate response to a wide repertoire of bacteria and viruses. Its response is usually thought to be proinflammatory rather than an antiviral. In monocytic cells TLR2 cooperates with coreceptors, e.g. CD14, CD36 and αMβ2-integrin. In an earlier work we showed that αvβ3-integrin acts in concert with TLR2 to elicit an innate response to HSV, and to lipopolysaccharide. This response is characterized by production of IFN-α and -β, a specific set of cytokines, and NF-κB activation. We investigated the basis of the cooperation between αvβ3-integrin and TLR2. We report that β3-integrin participates by signaling through Y residues located in the C-tail, known to be involved in signaling activity. αvβ3-integrin boosts the MYD88-dependent TLR2 signaling and IRAK4 phosphorylation in 293T and in epithelial, keratinocytic and neuronal cell lines. The replication of ICP0minus HSV is greatly enhanced by DN versions of MYD88, of Akt – a hub of this pathway, or by β3integrin-silencing. αvβ3-integrin enables the recruitment of TLR2, MAL, MYD88 at lipid rafts, the platforms from where the signaling starts. The PAMP of the HSV-induced innate response is the gH/gL virion glycoprotein, which interacts with αvβ3-integrin and TLR2 independently one of the other, and cross-links the two receptors. Given the preferential distribution of αvβ3-integrin to epithelial cells, we propose that αvβ3-integrin serves as coreceptor of TLR2 in these cells. The results open the possibility that TLR2 makes use of coreceptors in a variety of cells to broaden its spectrum of activity and tissue specificity.<br />Author Summary In an earlier work we showed that a relevant contribution to the overall IFN-based antiviral response of the cell to herpes simplex virus is exerted by αvβ3-integrin which acts in concert with TLR2 in eliciting this response. Major characteristics of this branch of the innate response are the secretion of IFN-α and -β, of a specific set of cytokines, and the activation of NF-κB. The response is elicited also by LPS, indicating that the αvβ3-integrin TLR2 sentinels sense both bacteria and viruses. The IFN response is usually thought to be elicited by the endosomal and cytoplasmic sensors. Here we have investigated the basis of the αvβ3-integrin–TLR2 response, and found that αvβ3-integrin acts through its signaling C-tail, and boosts the MYD88- IRAK4-dependent TLR2 response. This is seen also in epithelial and neuronal cells which exemplify targets of HSV infection. Altogether, the results argue that αvβ3-integrin may serve as a coreceptor of TLR2 in epithelial cells. A point of novelty is that the TLR2 coreceptors known to date - CD14, CD36 and αMβ2-integrins - are typical of monocytic-derived cells (macrophages, DCs). To our knowledge a TLR2 coreceptor for epithelial cells was not known to date.
- Subjects :
- lcsh:Immunologic diseases. Allergy
Keratinocytes
Immunology
Biology
Microbiology
Proinflammatory cytokine
Cell surface receptor
Virology
Genetics
Medicine and Health Sciences
Humans
Simplexvirus
Molecular Biology
lcsh:QH301-705.5
Neurons
Integrin alphaVbeta3
Bacteria
HEK 293 cells
Herpes Simplex
IRAK4
Toll-Like Receptor 2
Cell biology
TLR2
Interleukin-1 Receptor-Associated Kinases
lcsh:Biology (General)
Myeloid Differentiation Factor 88
herpes simplex virus, integrins
Parasitology
Signal transduction
lcsh:RC581-607
Proto-Oncogene Proteins c-akt
Research Article
HeLa Cells
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 10
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....8e9534f7f36cdbaa43184bd51ad175a2