Super-Resolution Fluorescence Imaging Reveals That Serine Incorporator Protein 5 Inhibits Human Immunodeficiency Virus Fusion by Disrupting Envelope Glycoprotein Clusters.
Super-Resolution Fluorescence Imaging Reveals That Serine Incorporator Protein 5 Inhibits Human Immunodeficiency Virus Fusion by Disrupting Envelope Glycoprotein Clusters.
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DOI：
10.1021/acsnano.0c02699
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发表时间：
2020-09-22
期刊：
影响因子：
17.1
通讯作者：
Melikyan GB
中科院分区：
文献类型：
--
作者：
Chen YC;Sood C;Marin M;Aaron J;Gratton E;Salaita K;Melikyan GB
丝氨酸掺入蛋白 5 (SERINC5) 是宿主抗逆转录病毒因子，可通过掺入病毒颗粒并抑制包膜糖蛋白 (Env) 介导的病毒与靶细胞融合来降低 HIV-1 感染性。我们和其他人已经证明，SERINC5 掺入病毒粒子会改变 Env 结构，并使病毒对针对隐性 Env 表位的广泛中和抗体敏感。我们还发现，与对照病毒相比，SERINC5 随着时间的推移会加速 Env 功能的丧失。然而，SERINC5 抑制 HIV-1 融合的确切机制尚不清楚。在这里，我们利用 2D 和 3D 超分辨率显微镜来检查 SERINC5 对单个 HIV-1 颗粒上 Env 糖蛋白分布的影响。我们发现，与之前的报告一致，Env 糖蛋白在成熟病毒粒子的表面形成簇。重要的是，掺入 SERINC5（而非缺乏抗病毒活性的 SERINC2）会破坏 Env 簇，但不会影响总体 Env 含量。我们还表明 SERINC5 和 SERINC2 也在单个病毒粒子上形成簇。出乎意料的是，Env 和 SERINCs 分子在病毒体上表现出较差的共分布，这可以通过 Env-SERINC 成对距离远大于 Env-Env 距离来证明。这一观察结果与之前报道的 Env 和 SERINC5 之间的相互作用不一致，表明 SERINC5 对 Env 簇形成的间接影响。总的来说，我们的结果揭示了 SERINC5 介导的 HIV-1 融合限制的多方面机制，除了对单个 Env 三聚体的影响之外，还涉及 Env 簇的破坏，而 Env 簇可能是病毒与靶细胞融合的位点。
Serine incorporator protein 5 (SERINC5) is the host anti-retroviral factor that reduces HIV-1 infectivity by incorporating into virions and inhibiting the envelope glycoprotein (Env) mediated virus fusion with target cells. We and others have shown that SERINC5 incorporation into virions alters the Env structure and sensitizes the virus to broadly neutralizing antibodies targeting cryptic Env epitopes. We have also found that SERINC5 accelerates the loss of Env function over time compared to control viruses. However, the exact mechanism by which SERINC5 inhibits HIV-1 fusion is not understood. Here, we utilized 2D and 3D super-resolution microscopy to examine the effect of SERINC5 on the distribution of Env glycoproteins on single HIV-1 particles. We find that, in agreement with a previous report, Env glycoproteins form clusters on the surface of mature virions. Importantly, incorporation of SERINC5, but not SERINC2, which lacks antiviral activity, disrupted Env clusters without affecting the overall Env content. We also show that SERINC5 and SERINC2 also form clusters on single virions. Unexpectedly, Env and SERINCs molecules exhibited poor co-distribution on virions, as evidenced by much greater Env-SERINC pairwise distances compare to Env-Env distances. This observation is inconsistent with the previously reported interaction between Env and SERINC5 and suggests an indirect effect of SERINC5 on Env cluster formation. Collectively, our results reveal a multifaceted mechanism of SERINC5-mediated restriction of HIV-1 fusion that, aside from the effects on individual Env trimers, involves disruption of Env clusters, which likely serve as sites of viral fusion with target cells.
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影响因子：
48
作者：
Dempsey, Graham T.;Vaughan, Joshua C.;Chen, Kok Hao;Bates, Mark;Zhuang, Xiaowei
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0511136103
发表时间：
2006-02-21
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
4.8
作者：
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