BCA2/Rabring7 Interferes with HIV-1 Proviral Transcription by Enhancing the SUMOylation of IκBα.
BCA2/Rabring7 Interferes with HIV-1 Proviral Transcription by Enhancing the SUMOylation of IκBα.
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DOI：
10.1128/jvi.02098-16
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发表时间：
2017-04-15
影响因子：
5.4
通讯作者：
Serra-Moreno R
中科院分区：
文献类型：
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作者：
Colomer-Lluch M;Serra-Moreno R
BCA2/Rabring7是一种BST2辅助因子，可促进捕获的HIV-1病毒粒子的溶酶体降解，但也可作为BST2独立的抗hiv因子，通过靶向Gag进行溶酶体降解。由于许多抗病毒因子调节NF-κB先天信号通路，我们研究了BCA2是否也与这种促炎级联反应有关。在这里，我们首次表明BCA2是由NF-κB活化的促炎细胞因子诱导的，并且BCA2的上调对NF-κB提供了调节性负反馈。具体来说，BCA2在i -κB α的SUMO化过程中作为E3 SUMO连接酶，从而增强细胞质中NF-κB成分的隔离。由于HIV-1利用NF-κB促进病毒前转录，bca2介导的NF-κB抑制显著降低HIV-1的转录活性（在CD4+ T细胞中高达4.4倍）。因此，我们的研究结果表明，BCA2对HIV-1感染具有额外的屏障作用：BCA2不仅阻止新生病毒粒子的组装和释放，还通过抑制NF-κB途径显著限制HIV-1转录。了解HIV-1与其宿主细胞之间的相互作用与设计旨在从感染个体中消除HIV-1的新药高度相关。我们之前已经证明BCA2， BST2在HIV-1限制中的辅助因子，也以BST2独立的方式阻止病毒粒子组装。在这项研究中，我们发现BCA2负调控NF-κB通路，这是HIV-1复制和感染所必需的信号级联，反过来对前病毒转录和病毒传播产生不利影响。因此，我们的研究结果表明，除了其先前描述的抗病毒因子的功能外，BCA2在转录水平上对HIV-1复制构成了额外的屏障。
BCA2/Rabring7 is a BST2 cofactor that promotes the lysosomal degradation of trapped HIV-1 virions but also functions as a BST2-independent anti-HIV factor by targeting Gag for lysosomal degradation. Since many antiviral factors regulate the NF-κB innate signaling pathway, we investigated whether BCA2 is also connected to this proinflammatory cascade. Here, we show for the first time that BCA2 is induced by NF-κB-activating proinflammatory cytokines and that upregulation of BCA2 provides regulatory negative feedback on NF-κB. Specifically, BCA2 serves as an E3 SUMO ligase in the SUMOylation of IκBα, which in turn enhances the sequestration of NF-κB components in the cytoplasm. Since HIV-1 utilizes NF-κB to promote proviral transcription, the BCA2-mediated inhibition of NF-κB significantly decreases the transcriptional activity of HIV-1 (up to 4.4-fold in CD4+ T cells). Therefore, our findings indicate that BCA2 poses an additional barrier to HIV-1 infection: not only does BCA2 prevent assembly and release of nascent virions, it also significantly restricts HIV-1 transcription by inhibiting the NF-κB pathway. IMPORTANCE Understanding the interactions between HIV-1 and its host cells is highly relevant to the design of new drugs aimed at eliminating HIV-1 from infected individuals. We have previously shown that BCA2, a cofactor of BST2 in the restriction of HIV-1, also prevents virion assembly in a BST2-independent manner. In this study, we found that BCA2 negatively regulates the NF-κB pathway—a signaling cascade necessary for HIV-1 replication and infectivity—which in turn detrimentally affects proviral transcription and virus propagation. Thus, our results indicate that, besides its previously described functions as an antiviral factor, BCA2 poses an additional barrier to HIV-1 replication at the transcriptional level.