The requirement of promyelocytic leukaemia protein (PML) in interferon (IFN)-induced cell apoptosis is well-established. However, the exact mechanisms by which the multiple isoforms of PML protein participate in this process remain not well-understood. We previously demonstrated that PML isoform II (PML-II) positively regulates induced gene expression during a type I IFN response and evaluate here how PML-II contributes to IFNα-induced cell death. HeLa cells were transiently depleted of PML-II by siRNA treatment and the response of these cells to treatment with IFNα assessed by molecular assays of mRNA and proteins associated with IFN and apoptosis responses. In HeLa cells, death during IFNα stimulation was reduced by prior PML-II depletion. PML-II removal also considerably decreased the induced expression of pro-apoptotic ISGs such as ISG54 (IFIT2), and substantially impaired or prevented expression of PUMA and TRAIL, proteins that are associated with the intrinsic and extrinsic apoptotic pathways respectively. Thirdly, PML-II depletion enhanced ERK and AKT pro-survival signaling activation suggesting that PML-II normally suppresses signaling via these pathways, and that lack of PML-II hence led to greater than normal activation of AKT signaling upon IFNα stimulation and consequently increased resistance to IFNα-induced apoptosis. The positive contribution of PML-II to the expression of various IFNα-induced pro-apoptotic proteins and its inhibition of pro-survival signaling together provide a mechanistic explanation for reduced apoptosis under conditions of PML deficiency and may account for at least part of the role of PML as a tumor suppressor gene.

中文翻译：

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PML-II 调节 ERK 和 AKT 信号激活和 IFNα 诱导的细胞死亡

早幼粒细胞白血病蛋白 (PML) 在干扰素 (IFN) 诱导的细胞凋亡中的需求是公认的。然而，PML 蛋白的多种亚型参与这一过程的确切机制仍未得到充分了解。我们之前证明了 PML 异构体 II (PML-II) 在 I 型 IFN 反应期间正向调节诱导的基因表达，并在此评估 PML-II 如何促进 IFNα 诱导的细胞死亡。HeLa 细胞通过 siRNA 处理瞬时耗尽 PML-II，这些细胞对 IFNα 处理的反应通过与 IFN 和细胞凋亡反应相关的 mRNA 和蛋白质的分子测定来评估。在 HeLa 细胞中，先前的 PML-II 消耗减少了 IFNα 刺激期间的死亡。PML-II 去除还显着降低了促凋亡 ISG 如 ISG54 (IFIT2) 的诱导表达，并显着损害或阻止了分别与内在和外在凋亡途径相关的蛋白质 PUMA 和 TRAIL 的表达。第三，PML-II 耗竭增强了 ERK 和 AKT 促生存信号激活，这表明 PML-II 通常抑制通过这些途径的信号传导，因此缺乏 PML-II 导致 AKT 信号在 IFNα 刺激时的激活大于正常，因此增加抗干扰素α诱导的细胞凋亡。