PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells
PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells
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DOI：
10.1073/pnas.1916054117
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发表时间：
2020-04-28
影响因子：
11.1
通讯作者：
Wu, Yuntao
中科院分区：
文献类型：
--
作者：
Fu, Yajing;He, Sijia;Wu, Yuntao
P-选择素糖蛋白配体-1是一种与P-选择素、E-选择素和L选择素结合的二聚体、粘蛋白样糖蛋白。PSGL-1主要在淋巴样细胞和髓样细胞表面表达，在炎症过程中上调，介导白细胞在内皮细胞表面的捆绑和滚动，从而迁移到炎症组织中。尽管已有报道PSGL-1的表达抑制了HIV-1的复制，但PSGL-1介导的抗HIV活性的机制仍有待阐明。在这里，我们报告了病毒粒子中的PSGL-1通过阻止粒子与靶细胞的结合来阻止HIV-1粒子的传染性。这种抑制活性不依赖于病毒颗粒上存在的病毒糖蛋白；PSGL-1会损害含有HIV-1包膜糖蛋白或水疱性口炎病毒G糖蛋白的颗粒的结合，甚至破坏缺乏病毒糖蛋白的颗粒的结合。图谱研究表明，PSGL-1的胞外N-末端结构域是其抗HIV-1活性所必需的，而PSGL-1的细胞质尾巴有助于抑制。此外，我们还证明了PSGL-1相关的E-选择素结合糖蛋白CD43也有效地阻断了HIV-1的感染性。HIV-1感染或VPU或Nef的表达下调了细胞表面的PSGL-1；VPU的表达似乎是使病毒部分逃脱PSGL-1介导的限制的主要原因。最后，我们发现PSGL-1可以抑制其他病毒的感染性，如小鼠白血病病毒和甲型流感病毒。这些发现表明PSGL-1是一种广谱抗病毒宿主因子，具有独特的作用机制。
P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is expressed primarily on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits HIV-1 replication, the mechanism of PSGL-1-mediated anti-HIV activity remains to be elucidated. Here we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein or vesicular stomatitis virus G glycoprotein or even lacking a viral glycoprotein is impaired by PSGL-1. Mapping studies show that the extracellular N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and that the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1-related monomeric E-selectin-binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, down-regulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses, such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a unique mechanism of action.