The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles
The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles
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DOI：
10.1074/jbc.m117.797332
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发表时间：
2017-08-18
影响因子：
4.8
通讯作者：
Fackler, Oliver T.
中科院分区：
文献类型：
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作者：
Trautz, Birthe;Wiedemann, Hannah;Fackler, Oliver T.
宿主细胞限制因子SERINC5能有效抑制HIV 1型（HIV-1）颗粒的感染性，并被病毒发病因子Nef抵消。然而，SERINC5限制HIV-1颗粒感染性的分子机制尚不清楚。由于serinc5蛋白被认为在膜脂的生物合成过程中促进丝氨酸的结合，并且由于HIV颗粒的脂质组成是颗粒感染潜力的主要决定因素，因此我们测试了serinc5介导的HIV颗粒感染性限制是否涉及膜脂组成的改变。我们从内源性SERINC5水平非常低的SERINC5293T细胞中产生并纯化了HIV-1颗粒，在异位表达SERINC5限制HIV-1感染并被Nef拮抗的条件下，用定量脂质ms分析了病毒粒子和产生细胞，SERINC5的限制和Nef的拮抗与产生细胞和HIV颗粒的稳态脂质组成的显著改变无关。鞘氨醇代谢动力学也不受SERINC5表达的影响。此外，在表达SERINC5或Nef时，HIV-1颗粒表面的磷脂酰丝氨酸水平并没有发生变化，而磷脂酰丝氨酸可能会触发靶细胞进入非生产性内化途径。最后，饱和HIV靶细胞上的磷脂酰丝氨酸结合位点不影响SERINC5限制或Nef拮抗剂。这些结果表明，SERINC5对HIV-1颗粒感染性的限制并不依赖于HIV-1颗粒的脂质组成和组织的改变，并表明将丝氨酸引导到脂质生物合成中可能不是SERINC5的主要细胞功能。
The host-cell restriction factor SERINC5 potently suppresses the infectivity of HIV, type 1 (HIV-1) particles, and is counteracted by the viral pathogenesis factor Nef. However, the molecular mechanism by which SERINC5 restricts HIV-1 particle infectivity is still unclear. Because SERINC proteins have been suggested to facilitate the incorporation of serine during the biosynthesis of membrane lipids and because lipid composition of HIV particles is a major determinant of the infectious potential of the particles, we tested whether SERINC5-mediated restriction of HIV particle infectivity involves alterations of membrane lipid composition. We produced and purified HIV-1 particles from SERINC5293T cells with very low endogenous SERINC5 levels under conditions in which ectopically expressed SERINC5 restricts HIV-1 infectivity and is antagonized by Nef and analyzed both virions and producer cells with quantitative lipid MS. SERINC5 restriction and Nef antagonism were not associated with significant alterations in steady-state lipid composition of producer cells and HIV particles. Sphingosine metabolism kinetics were also unaltered by SERINC5 expression. Moreover, the levels of phosphatidylserine on the surface of HIV-1 particles, which may trigger uptake into non-productive internalization pathways in target cells, did not change upon expression of SERINC5 or Nef. Finally, saturating the phosphatidylserine-binding sites on HIV target cells did not affect SERINC5 restriction or Nef antagonism. These results demonstrate that the restriction of HIV-1 particle infectivity by SERINC5 does not depend on alterations in lipid composition and organization of HIV-1 particles and suggest that channeling serine into lipid biosynthesis may not be a cardinal cellular function of SERINC5.