Serinc5 Restricts HIV Membrane Fusion by Altering Lipid Order and Heterogeneity in the Viral Membrane.
Serinc5 Restricts HIV Membrane Fusion by Altering Lipid Order and Heterogeneity in the Viral Membrane.
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Serinc5 通过改变病毒膜中的脂质顺序和异质性来限制 HIV 膜融合。
DOI：
10.1021/acsinfecdis.2c00478
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发表时间：
2023
影响因子：
5.3
通讯作者：
Tamm,LukasK
中科院分区：
文献类型：
--
作者：
Ward,AmandaE;Sokovikova,Daria;Waxham,MelvinNeal;Heberle,FrederickA;Levental,Ilya;Levental,KandiceR;Kiessling,Volker;White,JudithM;Tamm,LukasK
宿主限制因子Serinc 5可结合到萌芽的HIV颗粒中，并通过一种不完全了解的机制抑制其感染。我们以前曾报道Serinc 5而不是其paralysts Serinc 2通过膜融合阻断HIV细胞进入，特别是通过抑制融合孔的形成和扩张。大量的工作表明Serinc 5可能改变HIV融合蛋白Env的构象和聚集。为了对Serinc 5限制的发展模型提供额外的视角，我们评估了Serinc 2和Serinc 5对HIV假病毒膜的影响。通过测量假病毒膜厚度通过冷冻电子显微镜和顺序通过荧光染料，FLIPPER-TR，Serinc 5被发现增加膜的异质性，倾斜的分布朝向一个有序相的病毒膜的更大的部分。我们还首次直接观察到单个病毒膜包膜内膜结构域的共存。使用基于全内反射荧光的单颗粒融合测定，我们发现用磷脂酰乙醇胺（PE）处理HIV假病毒颗粒使HIV假病毒融合免于Serinc 5的限制，这伴随着膜异质性和有序性的降低。这种效果是特定的PE和不依赖于酰基链长度或饱和度。总之，这些数据表明Serinc 5改变了病毒膜的多个相互关联的特性-脂链顺序，刚性，线张力和侧压力-这降低了融合中间体的可及性，不利于融合的完成。这些对Serinc 5限制HIV感染性的生物物理学见解可能有助于开发利用相同弱点的新型抗病毒药物。
The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5’s effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, FLIPPER-TR, Serinc5 was found to increase membrane heterogeneity, skewing the distribution toward a larger fraction of the viral membrane in an ordered phase. We also directly observed for the first time the coexistence of membrane domains within individual viral membrane envelopes. Using a total internal reflection fluorescence-based single particle fusion assay, we found that treatment of HIV pseudoviral particles with phosphatidylethanolamine (PE) rescued HIV pseudovirus fusion from restriction by Serinc5, which was accompanied by decreased membrane heterogeneity and order. This effect was specific for PE and did not depend on acyl chain length or saturation. Together, these data suggest that Serinc5 alters multiple interrelated properties of the viral membrane─lipid chain order, rigidity, line tension, and lateral pressure─which decrease the accessibility of fusion intermediates and disfavor completion of fusion. These biophysical insights into Serinc5 restriction of HIV infectivity could contribute to the development of novel antivirals that exploit the same weaknesses.
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DOI：
10.3390/v14081636
发表时间：
2022-07-27
期刊：
Viruses
影响因子：
--
作者：
通讯作者：
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Toshiyuki Shinji 等人：细胞结构和功能。
DOI：
--
发表时间：
--
期刊：
影响因子：
--
作者：
通讯作者：
--
影响因子：
17.1
作者：
Chen YC;Sood C;Marin M;Aaron J;Gratton E;Salaita K;Melikyan GB
通讯作者：
Melikyan GB
影响因子：
3.4
作者：
Ionova, Irina V.;Livshits, Vsevolod A.;Marsh, Derek
通讯作者：
Marsh, Derek
DOI：
10.1016/j.bbamem.2016.09.010
发表时间：
2016-12
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
O'Neil L;Andenoro K;Pagano I;Carroll L;Langer L;Dell Z;Perera D;Treece BW;Heinrich F;Lösche M;Nagle JF;Tristram-Nagle S
通讯作者：
Tristram-Nagle S