The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5
The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5
复制标题
逆转录病毒辅助蛋白 S2、Nef 和 gluMA 使用类似的机制来拮抗宿主限制因子 SERINC5
DOI：
10.1074/jbc.ra119.007662
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发表时间：
2019-04-26
影响因子：
4.8
通讯作者：
Zheng, Yong-Hui
中科院分区：
文献类型：
--
作者：
Ahmad, Iqbal;Li, Sunan;Zheng, Yong-Hui
丝氨酸蛋白酶5（SERINC 5）是最近发现的一种限制性因子，可阻断病毒进入，但可被三种不相关的逆转录病毒辅助蛋白拮抗。马传染性贫血病毒（EIAV）的S2蛋白已被报道可能通过内吞途径降低稳态水平的SERINC 5表达;然而，确切的机制仍不清楚。在这里，我们研究了EIAV S2蛋白如何下调SERINC 5与来自HIV-1的Nef和来自小鼠白血病病毒（MLV）的glycoMA蛋白诱导的下调相比。利用双分子荧光互补（BiFC）和免疫沉淀（IP）技术，我们检测到了S2和SERINC 5之间的相互作用。我们发现这种相互作用依赖于S2豆蔻酰化位点，表明它可能发生在质膜上。S2通过受体介导的内吞作用内化SERINC 5，并将其靶向至内体和溶酶体，导致SERINC 5表达在稳态水平下的泛素化依赖性降低。BiFC和IP均检测到glycoMA-SERINC 5相互作用，但仅BiFC检测到Nef-SERINC 5相互作用。此外，S2和glycoMA下调SERINC 5比Nef更有效。我们进一步表明，与Nef不同，S2和glycoMA都有效地下调了热带爪蟾的SERINC 2和SERINC 5（xSERINC 5）。此外，我们检测了马SERINC 5（eSERINC 5）蛋白的表达，并观察到其表达比其他物种的SERINC 5表达水平弱得多。尽管如此，eSERINC 5具有很强的抗病毒活性，可被S2有效抵消。我们的结论是，HIV-1，EIAV和MLV共享一个类似的机制，拮抗病毒限制宿主SERINC 5。
Serine incorporator 5 (SERINC5) is a recently identified restriction factor that blocks virus entry but is antagonized by three unrelated retroviral accessory proteins. The S2 protein from equine infectious anemia virus (EIAV) has been reported to reduce SERINC5 expression at steady-state levels likely via the endocytic pathway; however, the precise mechanism is still unclear. Here, we investigated how EIAV S2 protein down-regulates SERINC5 compared with down-regulation induced by Nef from HIV-1 and glycoMA proteins from murine leukemia virus (MLV). Using bimolecular fluorescence complementation (BiFC) assay and immunoprecipitation (IP), we detected an interaction between S2 and SERINC5. We found that this interaction relies on the S2 myristoylation site, indicating that it may occur on the plasma membrane. S2 internalized SERINC5 via receptor-mediated endocytosis and targeted it to endosomes and lysosomes, resulting in a ubiquitination-dependent decrease in SERINC5 expression at steady-state levels. Both BiFC and IP detected a glycoMA-SERINC5 interaction, but a Nef-SERINC5 interaction was detected only by BiFC. Moreover, S2 and glycoMA down-regulated SERINC5 more effectively than did Nef. We further show that unlike Nef, both S2 and glycoMA effectively down-regulate SERINC2 and also SERINC5 from Xenopus tropicalis (xSERINC5). Moreover, we detected expression of the equine SERINC5 (eSERINC5) protein and observed that its expression is much weaker than expression levels of SERINC5 from other species. Nonetheless, eSERINC5 had a strong antiviral activity that was effectively counteracted by S2. We conclude that HIV-1, EIAV, and MLV share a similar mechanism to antagonize viral restriction by host SERINC5.