Slit2N/Robo1 inhibit HIV-gp120-induced migration and podosome formation in immature dendritic cells by sequestering LSP1 and WASp.
Slit2N/Robo1 inhibit HIV-gp120-induced migration and podosome formation in immature dendritic cells by sequestering LSP1 and WASp.
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Slit2N/Robo1 通过隔离 LSP1 和 WASp 来抑制 HIV-gp120 诱导的未成熟树突状细胞的迁移和足小体形成。
DOI：
10.1371/journal.pone.0048854
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Groopman JE
中科院分区：
文献类型：
--
作者：
Prasad A;Kuzontkoski PM;Shrivastava A;Zhu W;Li DY;Groopman JE
细胞介导的性获得性人类免疫缺陷病毒1（HIV-1）在宿主中的传播和散布涉及未成熟树突状细胞（iDC）的迁移。iDC响应HIV-1包膜蛋白gp 120而迁移，抑制这种迁移可限制HIV-1的粘膜传播。在这项研究中，我们阐明了HIV-1-gp 120诱导的iDCs跨内皮迁移的机制。我们发现，gp 120增强了Wiskott-Aldrich综合征蛋白（WASp）和肌动蛋白相关蛋白2/3（Arp 2/3）复合物与β-肌动蛋白的结合，这是一种对于适当形成podosomes必不可少的相互作用，podosomes是iDC通过不同组织迁移所需的专门粘附结构。我们进一步鉴定了白细胞特异性蛋白1（LSP 1）作为WASp-Arp 2/3-β-actin复合物的新组分。用分泌性糖蛋白Slit 2的活性片段（Slit 2N）预处理iDC通过诱导同源受体Roundabout 1（Robo 1）与β-肌动蛋白结合并隔离WASp和LSP 1来抑制HIV-1-gp 120介导的迁移和podosome形成。Slit 2N处理还抑制Src信号传导和几种下游分子的活化，包括Rac 1、Pyk 2、桩蛋白和CDC 42，CDC 42是podosome形成的主要调节因子。综上所述，我们的研究结果支持一种新的机制，通过该机制Slit 2/Robo 1可以抑制HIV-1-gp 120诱导的iDCs迁移，从而限制HIV-1从宿主粘膜表面的传播。
Cell-mediated transmission and dissemination of sexually-acquired human immunodeficiency virus 1 (HIV-1) in the host involves the migration of immature dendritic cells (iDCs). iDCs migrate in response to the HIV-1 envelope protein, gp120, and inhibiting such migration may limit the mucosal transmission of HIV-1. In this study, we elucidated the mechanism of HIV-1-gp120-induced transendothelial migration of iDCs. We found that gp120 enhanced the binding of Wiskott-Aldrich Syndrome protein (WASp) and the Actin-Related Protein 2/3 (Arp2/3) complex with β-actin, an interaction essential for the proper formation of podosomes, specialized adhesion structures required for the migration of iDCs through different tissues. We further identified Leukocyte-Specific Protein 1 (LSP1) as a novel component of the WASp-Arp2/3-β-actin complex. Pretreating iDCs with an active fragment of the secretory glycoprotein Slit2 (Slit2N) inhibited HIV-1-gp120-mediated migration and podosome formation, by inducing the cognate receptor Roundabout 1 (Robo1) to bind to and sequester WASp and LSP1 from β-actin. Slit2N treatment also inhibited Src signaling and the activation of several downstream molecules, including Rac1, Pyk2, paxillin, and CDC42, a major regulator of podosome formation. Taken together, our results support a novel mechanism by which Slit2/Robo1 may inhibit the HIV-1-gp120-induced migration of iDCs, thereby restricting dissemination of HIV-1 from mucosal surfaces in the host.
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影响因子：
64.5
作者：
Brose, K;Bland, KS;Kidd, T
通讯作者：
Kidd, T
DOI：
10.1084/jem.192.4.587
发表时间：
2000-08-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lin CL;Sewell AK;Gao GF;Whelan KT;Phillips RE;Austyn JM
通讯作者：
Austyn JM
影响因子：
3.3
作者：
Destaing, O;Saltel, F;Bard, F
通讯作者：
Bard, F
影响因子：
4.4
作者：
Huminiecki, L;Gorn, M;Bicknell, R
通讯作者：
Bicknell, R
影响因子：
4.4
作者：
Chen, B;Blair, DG;Yang, D
通讯作者：
Yang, D