Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts.
Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts.
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DOI：
10.1158/1541-7786.mcr-10-0565
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发表时间：
2011-05
期刊：
影响因子：
--
通讯作者：
Choubey D
中科院分区：
文献类型：
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作者：
Duan X;Ponomareva L;Veeranki S;Panchanathan R;Dickerson E;Choubey D
干扰素（IFN）诱导的IFI 16和AIM 2蛋白作为细胞溶质双链DNA（dsDNA）的先天免疫传感器。在感测dsDNA时，IFI 16蛋白诱导IFN-β的表达，而AIM 2蛋白形成炎性体，其促进IL-1β的分泌。鉴于人二倍体成纤维细胞（HDF）中IFI 16表达的敲低延迟了细胞衰老的开始，我们研究了IFI 16和AIM 2蛋白在细胞衰老中的潜在作用。我们发现老年人（与年轻人相比）HDFs中IFI 16蛋白水平的增加与IFN-β的诱导有关。相比之下，衰老（相对于老年）HDF中AIM 2蛋白水平的增加与IL-1β产生的增加相关。I型IFN-受体亚基-α的敲除降低了IFI 16的基础水平，但不降低AIM 2蛋白的基础水平，从而延迟了细胞衰老的开始。因此，共济失调毛细血管扩张（AT）HDF中IFI 16和AIM 2蛋白组成性水平的增加与IFN信号传导的激活和IL-1β水平的增加相关。IFN-β处理年轻的HDFs，诱导IFI 16和AIM 2蛋白的表达，激活DNA损伤反应，也增加了IL-1β的基础水平。有趣的是，HDFs中AIM 2表达的敲低增加了IFI 16蛋白的基础水平并激活了IFN信号传导。相反，在HDF中IFI 16表达的敲低降低了IFN信号传导的基础和dsDNA诱导的活化。总的来说，我们的观察表明IFI 16和AIM 2蛋白在细胞衰老和相关分泌表型中的不同作用。
The interferon (IFN)-inducible IFI16 and AIM2 proteins act as innate immune sensors for cytosolic double-stranded DNA (dsDNA). Upon sensing dsDNA, the IFI16 protein induces the expression of IFN-β whereas the AIM2 protein forms an inflammasome, which promotes the secretion of IL-1β. Given that the knockdown of IFI16 expression in human diploid fibroblasts (HDFs) delays the onset of cellular senescence, we investigated the potential roles for the IFI16 and AIM2 proteins in cellular senescence. We found that increased IFI16 protein levels in old (versus young) HDFs were associated with the induction of IFN-β. In contrast, increased levels of the AIM2 protein in the senescent (versus old) HDFs were associated with increased production of IL-1β. The knockdown of type I IFN-receptor subunit-α, which reduced the basal levels of the IFI16, but not the AIM2, protein delayed the onset of cellular senescence. Accordingly, increased constitutive levels of IFI16 and AIM2 proteins in ataxia telangiectasia (AT) HDFs were associated with the activation of the IFN-signaling and increased levels of IL-1β. The IFN-β treatment of the young HDFs, which induced the expression of IFI16 and AIM2 proteins, activated a DNA-damage response and also increased basal levels of IL-1β. Interestingly, the knockdown of AIM2 expression in HDFs increased the basal levels of IFI16 protein and activated the IFN-signaling. In contrast, the knockdown of the IFI16 expression in HDFs decreased the basal and dsDNA-induced activation of the IFN-signaling. Collectively, our observations demonstrate differential roles for the IFI16 and AIM2 proteins in cellular senescence and associated secretory phenotype.