CVB3 Nonstructural 2A Protein Modulates SREBP1a Signaling via the MEK/ERK Pathway
CVB3 Nonstructural 2A Protein Modulates SREBP1a Signaling via the MEK/ERK Pathway
复制标题
CVB3 非结构 2A 蛋白通过 MEK/ERK 途径调节 SREBP1a 信号传导。
DOI：
10.1128/jvi.01060-18
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发表时间：
2018-12-01
影响因子：
5.4
通讯作者：
Zhang, Kebin
中科院分区：
文献类型：
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作者：
Wang, Lei;Xie, Wei;Zhang, Kebin
柯萨奇病毒B3(CVB3)是病毒性心肌炎的主要病原体。在我们之前的研究中，我们发现CVB3会导致宿主细胞中的异常脂质积聚。然而，CVB3干扰和利用宿主脂代谢的潜在机制尚不清楚。固醇调节元件结合蛋白1(SREBP1)是成脂基因表达的主要转录因子。在这项研究中，我们证明了CVB3感染和非结构蛋白2A在转录水平上上调和激活了SREBP1a。SREBP1a启动子的缺失分析表明，该启动子中的-1821/-1490和-312/+217两个区域都是其被2A激活所必需的。这些启动子区域具有几个与转录因子SP1结合的基序。接下来，我们使用SP1特异的小干扰RNA(SiRNAs)来证实SP1可能是SREBP1a上调2A的关键因素。此外，我们还发现MEK/ERK通路参与了2A对SREBP1a的激活，而用特异性抑制剂U0126阻断该信号通路可抑制2A对SREBP1a的激活和脂质积累。最后，我们发现，用siRNAs抑制SREBP1可以减轻CVB3感染引起的脂质堆积，并减少病毒复制。此外，抑制MEK/ERK通路还导致CVB3感染过程中SREBP1a活化、脂质积累和病毒复制的减少。综上所述，这些数据表明，CVB3非结构蛋白2A蛋白通过MEK/ERK信号通路和SP1转录因子在转录水平激活SREBP1a，促进细胞脂质积累，有利于病毒复制。重要的是，柯萨奇病毒B3(CVB3)感染是病毒性心肌炎的主要原因，但仍缺乏有效的疫苗和抗病毒治疗。了解宿主和病毒之间的精确相互作用对于合理设计有效的治疗方法是很重要的。在感染过程中，CVB3破坏并利用宿主的脂肪代谢促进过多的脂肪积累，从而有利于病毒复制。SREBP1是细胞脂代谢的主要调节者。在这里，我们报告了一种病毒非结构蛋白2A上调并激活SREBP1a。此外，我们发现抑制SREBP1降低了CVB3病毒的复制。这些结果揭示了2A对SREBP1a表达的调节以及SREBP1在CVB3感染过程中的脂质积累和病毒复制中的作用。我们的发现为CVB3宿主相互作用提供了新的见解，并为这种重要病原体的潜在治疗靶点提供了信息。
Coxsackievirus B3 (CVB3) is the predominant pathogen of viral myocarditis. In our previous study, we found that CVB3 caused abnormal lipid accumulation in host cells. However, the underlying mechanisms by which CVB3 disrupts and exploits the host lipid metabolism are not well understood. Sterol regulatory element binding protein 1 (SREBP1) is the major transcriptional factor in lipogenic genes expression. In this study, we demonstrated that CVB3 infection and nonstructural 2A protein upregulated and activated SREBP1a at the transcriptional level. Deletion analysis of SREBP1a promoter revealed that two regions, -1821/-1490 and -312/+217, in this promoter were both required for its activation by 2A. These promoter regions possessed several binding motifs for transcription factor SP1. Next, we used SP1-specific small interfering RNAs (siRNAs) to confirm that SP1 might be the essential factor in SREBP1a upregulation by 2A. Furthermore, we showed that MEK/ERK pathway was involved in the activation of SREBP1a by 2A and that blocking this signaling pathway with the specific inhibitor U0126 attenuated SREBP1a activation and lipid accumulation by 2A. Finally, we showed that inhibition of SREBP1 with siRNAs attenuated lipid accumulation induced by CVB3 infection and reduced virus replication. Moreover, inhibition of the MEK/ERK pathway also led to reduction of SREBP1a activation, lipid accumulation, and virus replication during CVB3 infection. Taken together, these data demonstrate that CVB3 nonstructural 2A protein activates SREBP1a at the transcription level through a mechanism involving MEK/ERK signaling pathway and SP1 transcription factor, which promotes cellular lipid accumulation and benefits virus replication.IMPORTANCE Coxsackievirus B3 (CVB3) infection is the leading cause of viral myocarditis, but effective vaccines and antiviral therapies against CVB3 infection are still lacking. It is important to understand the precise interactions between host and virus for the rational design of effective therapies. During infection, CVB3 disrupts and exploits host lipid metabolism to promote excessive lipid accumulation, which benefits virus replication. SREBP1 is the master regulator of cellular lipid metabolism. Here, we report that one of the viral nonstructural proteins, 2A, upregulates and activates SREBP1a. Furthermore, we find that inhibition of SREBP1 decreases CVB3 virus replication. These results reveal the regulation of SREBP1a expression by 2A and the roles of SREBP1 in lipid accumulation and viral replication during CVB3 infection. Our findings provide a new insight into CVB3 host interactions and inform a potential novel therapeutic target for this important pathogen.