The epithelial αvβ3-integrin boosts the MYD88-dependent TLR2 signaling in response to viral and bacterial components.
The epithelial αvβ3-integrin boosts the MYD88-dependent TLR2 signaling in response to viral and bacterial components.
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DOI：
10.1371/journal.ppat.1004477
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发表时间：
2014-11
期刊：
影响因子：
6.7
通讯作者：
Campadelli-Fiume G
中科院分区：
文献类型：
--
作者：
Gianni T;Campadelli-Fiume G
TLR 2是一种细胞表面受体，其激发对广泛的细菌和病毒库的立即应答。它的反应通常被认为是促炎而不是抗病毒。在单核细胞中，TLR 2与辅助受体如CD 14、CD 36和αMβ2-整联蛋白协同作用。在早期的工作中，我们发现αvβ3-整联蛋白与TLR 2协同作用，引起对HSV和脂多糖的先天性应答。这种应答的特征在于产生IFN-α和IFN-β（一组特异性细胞因子）以及NF-κB活化。我们研究了αvβ3-整合素与TLR 2之间相互作用的基础。我们报道了β3-整联蛋白通过位于C-尾的Y残基参与信号传导，已知Y残基参与信号传导活性。αvβ3-整联蛋白增强293 T以及上皮、角质形成细胞和神经元细胞系中MYD 88依赖性TLR 2信号传导和IRAK 4磷酸化。ICP 0减HSV的复制被DN形式的MYD 88、Akt（该途径的枢纽）或β 3整联蛋白沉默极大地增强。αvβ3-整联蛋白使TLR 2、MAL、MYD 88能够在脂筏上募集，脂筏是信号传导开始的平台。HSV诱导的先天性应答的PAMP是gH/gL病毒体糖蛋白，其与αvβ3-整联蛋白和TLR 2相互独立地相互作用，并交联两种受体。鉴于αvβ3-整合素在上皮细胞中的优先分布，我们认为αvβ3-整合素在这些细胞中充当TLR 2的辅助受体。这些结果开启了TLR 2利用多种细胞中的辅助受体来拓宽其活性谱和组织特异性的可能性。在早期的工作中，我们发现αvβ3-整联蛋白对细胞对单纯疱疹病毒的总体基于IFN的抗病毒应答有相关贡献，αvβ3-整联蛋白与TLR 2协同作用引发这种应答。该先天性应答分支的主要特征是分泌IFN-α和IFN-β、一组特定的细胞因子以及激活NF-κB。LPS也能引起这种反应，表明αvβ3-整联蛋白TLR 2哨兵可以同时检测细菌和病毒。IFN应答通常被认为是由内体和细胞质传感器引起的。在这里，我们研究了αvβ3-整联蛋白-TLR 2应答的基础，发现αvβ3-整联蛋白通过其信号传导C-尾起作用，并增强MYD 88-IRAK 4依赖性TLR 2应答。这也见于上皮细胞和神经元细胞中，它们是HSV感染的靶细胞。总之，结果表明，αvβ3-整合素可能作为TLR 2在上皮细胞中的辅助受体。新奇之处在于，迄今已知的TLR 2辅助受体-CD 14、CD 36和αMβ2-整联蛋白-是单核细胞衍生细胞（巨噬细胞，DC）的典型受体。据我们所知，迄今为止尚不清楚上皮细胞的TLR 2辅助受体。
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. 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.
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影响因子：
11.8
作者：
Heit, Bryan;Kim, Hani;Cosio, Gabriela;Castano, Diana;Collins, Richard;Lowell, Clifford A.;Kain, Kevin C.;Trimble, William S.;Grinstein, Sergio
通讯作者：
Grinstein, Sergio
影响因子：
5.9
作者：
Campadelli-Fiume, Gabriella;Menotti, Laura;Gianni, Tatiana
通讯作者：
Gianni, Tatiana
影响因子：
5.4
作者：
Eaton, Heather E.;Saffran, Holly A.;Smiley, James R.
通讯作者：
Smiley, James R.
影响因子：
5.4
作者：
Gregory, D;Hargett, D;Bachenheimer, SL
通讯作者：
Bachenheimer, SL
DOI：
10.1073/pnas.1323414111
发表时间：
2014-02-04
影响因子：
11.1
作者：
Kalamvoki, Maria;Roizman, Bernard
通讯作者：
Roizman, Bernard