Two distinct phases of virus-induced nuclear factor κB regulation enhance tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in virus-infected cells
Two distinct phases of virus-induced nuclear factor κB regulation enhance tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in virus-infected cells
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DOI：
10.1074/jbc.m300265200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Tyler, KL
中科院分区：
文献类型：
--
作者：
Clarke, P;Meintzer, SM;Tyler, KL
细胞转录因子通常被感染病毒用来促进病毒生长并影响细胞命运。我们以前已经表明，核因子κ B（NF-κ B）被激活后呼肠孤病毒感染，这种激活是病毒诱导的细胞凋亡所必需的。在这份报告中，我们确定了呼肠孤病毒诱导的NF-κ B调节的第二阶段。我们发现，在感染后的时间NF-κ B激活被阻断在呼肠孤病毒感染的细胞。这导致病毒诱导的NF-κ B活性的终止以及肿瘤坏死因子α和依托泊苷诱导的感染细胞中NF-κ B活化的抑制。呼肠孤病毒诱导的NF-κ B活化抑制通过防止IkappaB α降解的机制发生，并且在病毒RNA合成抑制剂利巴韦林存在下被阻断。呼肠孤病毒诱导的细胞凋亡是由肿瘤坏死因子相关凋亡诱导配体（TRAIL）介导的多种上皮细胞系。在此，我们表明利巴韦林抑制呼肠孤病毒诱导的凋亡的TRAIL-抗性HEK 293细胞，并阻止呼肠孤病毒感染的能力，敏感的TRAIL-抗性细胞的TRAIL-诱导的凋亡。此外，TRAIL诱导的细胞凋亡在表达IkappaBDeltaN 2的HEK 293细胞中增强，IkappaBDeltaN 2阻断NF-κ B活化。这些结果表明，呼肠孤病毒抑制NF-κ B活化的能力使HEK 293细胞对TRAIL敏感，并促进病毒诱导的TRAIL抗性细胞凋亡。我们的研究结果表明，需要病毒诱导的NF-kappaB调节的两个不同阶段才能有效激活宿主细胞对呼肠孤病毒感染的凋亡反应。
Cellular transcription factors are often utilized by infecting viruses to promote viral growth and influence cell fate. We have previously shown that nuclear factor kappaB (NF-kappaB) is activated after reovirus infection and that this activation is required for virus-induced apoptosis. In this report we identify a second phase of reovirus-induced NF-kappaB regulation. We show that at later times post-infection NF-kappaB activation is blocked in reovirus-infected cells. This results in the termination of virus-induced NF-kappaB activity and the inhibition of tumor necrosis factor alpha and etoposide-induced NF-kappaB activation in infected cells. Reovirus-induced inhibition of NF-kappaB activation occurs by a mechanism that prevents IkappaBalpha degradation and that is blocked in the presence of the viral RNA synthesis inhibitor, ribavirin. Reovirus-induced apoptosis is mediated by tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in a variety of epithelial cell lines. Herein we show that ribavirin inhibits reovirus-induced apoptosis in TRAIL-resistant HEK293 cells and prevents the ability of reovirus infection to sensitize TRAIL-resistant cells to TRAIL-induced apoptosis. Furthermore, TRAIL-induced apoptosis is enhanced in HEK293 cells expressing IkappaBDeltaN2, which blocks NF-kappaB activation. These results indicate that the ability of reovirus to inhibit NF-kappaB activation sensitizes HEK293 cells to TRAIL and facilitates virus-induced apoptosis in TRAIL-resistant cells. Our findings demonstrate that two distinct phases of virus-induced NF-kappaB regulation are required to efficiently activate host cell apoptotic responses to reovirus infection.