Cyclophilin A binds to AKT1 and facilitates the tumorigenicity of Epstein-Barr virus by mediating the activation of AKT/mTOR/NF-κB positive feedback loop.
Cyclophilin A binds to AKT1 and facilitates the tumorigenicity of Epstein-Barr virus by mediating the activation of AKT/mTOR/NF-κB positive feedback loop.
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DOI：
10.1016/j.virs.2022.09.001
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发表时间：
2022-12
影响因子：
5.5
通讯作者：
Lu, Jianhong
中科院分区：
文献类型：
--
作者：
Xin, Shuyu;Liu, Lingzhi;Li, Yanling;Yang, Jing;Zuo, Lielian;Cao, Pengfei;Yan, Qijia;Li, Shen;Yang, Li;Cui, Taimei;Lu, Jianhong
关键词：
AKT/mTOR和NF-κB信号通路是包括鼻咽癌（NPC）在内的多种肿瘤中激活的重要通路，鼻咽癌在中国南方多见，与EB病毒（EBV）感染密切相关。这些主通路如何在EBV相关NPC中持续激活仍有待研究。在此，我们证明EBV编码的潜伏膜蛋白1（LMP 1）通过激活NF-κB促进亲环素A（CYPA）的表达。CYPA的耗竭抑制细胞增殖并促进凋亡。CYPA能够与AKT 1结合，从而激活AKT/mTOR/NF-κB信号级联。此外，mTOR抑制剂雷帕霉素的使用破坏了正反馈环NF-κB/CYPA/AKT/mTOR的激活。因此，由初始病毒感染引起的LMP 1表达足以确保AKT/mTOR和NF-κB信号转导的持续增强是合理的。这可能部分解释了EBV作为肿瘤促进因子，在恶性肿瘤中病毒癌蛋白LMP 1表达最低的事实。我们的研究结果提供了新的见解，了解潜伏感染过程中的致瘤性EBV的致病作用。EBV-LMP 1通过NF-κB活化促进亲环素A（CYPA）表达。CYPA与AKT 1结合，激活AKT/mTOR/NF-κB信号级联。EBV驱动致癌NF-κB/CYPA/AKT/mTOR/NF-κB正反馈环。癌环激活中不必要的持续LMP 1表达可能有助于病毒逃避宿主监视。
The AKT/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma (NPC), which is prevalent in southern China and closely related to Epstein-Barr virus (EBV) infection. How these master pathways are persistently activated in EBV-associated NPC remains to be investigated. Here we demonstrated that EBV-encoded latent membrane protein 1 (LMP1) promoted cyclophilin A (CYPA) expression through the activation of NF-κB. The depletion of CYPA suppressed cell proliferation and facilitated apoptosis. CYPA was able to bind to AKT1, thus activating AKT/mTOR/NF-κB signaling cascade. Moreover, the use of mTOR inhibitor, rapamycin, subverted the activation of the positive feedback loop, NF-κB/CYPA/AKT/mTOR. It is reasonable that LMP1 expression derived from initial viral infection is enough to assure the constant potentiation of AKT/mTOR and NF-κB signalings. This may partly explain the fact that EBV serves as a tumor-promoting factor with minimal expression of the viral oncoprotein LMP1 in malignancies. Our findings provide new insight into the understanding of causative role of EBV in tumorigenicity during latent infection. EBV-LMP1 promotes cyclophilin A (CYPA) expression via NF-κB activation. CYPA binds to AKT1 to activate AKT/mTOR/NF-κB signaling cascade. EBV drives oncogenic NF-κB/CYPA/AKT/mTOR/NF-κB positive feedback loop. Unwanted persistent LMP1 expression in the onco-loop activation may help viral evasion from host surveillance.
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