期刊
PLOS PATHOGENS
卷 10, 期 11, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1004477
关键词
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资金
- ERC [340060]
- Italian Association for Cancer Research (AIRC)
- University of Bologna RFO (Ricerca Fondamentale Orientata)
- Italian Ministry for University and Research (PRIN project)
- Pallotti Funds from our Department
- European Research Council (ERC) [340060] Funding Source: European Research Council (ERC)
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 alpha M beta 2-integrin. In an earlier work we showed that alpha v beta 3-integrin acts in concert with TLR2 to elicit an innate response to HSV, and to lipopolysaccharide. This response is characterized by production of IFN-alpha and -beta, a specific set of cytokines, and NF-kappa B activation. We investigated the basis of the cooperation between alpha v beta 3-integrin and TLR2. We report that beta 3-integrin participates by signaling through Y residues located in the C-tail, known to be involved in signaling activity. alpha v beta 3-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 beta 3integrin-silencing. alpha v beta 3-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 alpha v beta 3-integrin and TLR2 independently one of the other, and cross-links the two receptors. Given the preferential distribution of alpha v beta 3-integrin to epithelial cells, we propose that alpha v beta 3-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.
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