Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Virology. 2018 Sep;522:106-121. doi: 10.1016/j.virol.2018.07.007. Epub 2018 Jul 17.
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) vFLIP, a latent gene of KSHV, was first identified as a FLICE-inhibitory protein (FLIP) protecting cells from apoptosis. The vFLIP protein has been shown to activate the NF-κB signaling involved in spindle morphology formation both in HUVECs infected with KSHV and Kaposi's sarcoma (KS) itself. In this study, we independently established stably vFLIP-expressing cells and showed that they exhibited upregulated NF-κB family protein expression independent of the ability of IKKs to bind vFLIP. Further, vFLIP induced upregulation of IKKε, phosphorylation of RelA at Ser468 (p-RelA S468) and nuclear localization of Re1A concomitant with spindle morphology formation, and these effects were reversed by knockdown of IKKε and treatment with Bay-11. Overexpression of IKKε alone also showed spindle morphology formation with p-RelA S468. In conclusion, the spindle cell morphology in KS should be induced by RelA activation (p-RelA S468) by IKKε upregulation in vFLIP-expressing EA hy926 cells.
卡波济肉瘤相关疱疹病毒（KSHV）的 vFLIP，是 KSHV 的一个潜伏基因，最初被鉴定为一种能够保护细胞免受凋亡的 FLICE 抑制蛋白（FLIP）。vFLIP 蛋白已被证明能够激活 NF-κB 信号通路，该通路参与了受 KSHV 感染的人脐静脉内皮细胞（HUVEC）和卡波济肉瘤（KS）本身的纺锤体形态形成。在这项研究中，我们独立建立了稳定表达 vFLIP 的细胞，并表明它们表现出 NF-κB 家族蛋白表达的上调，而与 IKKs 结合 vFLIP 的能力无关。此外，vFLIP 诱导 IKKε 的上调、RelA 在 Ser468 位的磷酸化（p-RelA S468）以及 RelA 的核定位与纺锤体形态形成同时发生，这些效应可以通过 IKKε 的敲低和 Bay-11 的处理来逆转。单独过表达 IKKε 也显示出 p-RelA S468 的纺锤体形态形成。总之，在 vFLIP 表达的 EA hy926 细胞中，RelA 激活（p-RelA S468）通过 IKKε 的上调诱导了 KS 中的纺锤体细胞形态。
