Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes
Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes
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DOI：
10.1073/pnas.0903487106
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发表时间：
2009-06-09
影响因子：
11.1
通讯作者：
Stark, George R.
中科院分区：
文献类型：
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作者：
Cheon, HyeonJoo;Stark, George R.
在用干扰素 (IFN) 处理的正常人体细胞中，驱动大量基因表达的酪氨酸磷酸化 STAT1 (YP-STAT1) 浓度迅速增加，但随后在几个小时内下降。由于 STAT1 基因被 YP-STAT1 激活，因此 IFN 会刺激未磷酸化 STAT1 (U-STAT1) 浓度大幅增加，并持续数天。为了测试 U-STAT1 高表达的意义，我们在没有 IFN 治疗的情况下外源增加其浓度。作为回应，许多免疫调节基因（例如 IFI27、IFI44、OAS 和 BST2）的表达增加。在用低浓度的 IFN-β 或 IFN-γ 处理的人成纤维细胞或乳腺上皮细胞中，相同基因的表达在 6 小时后增加，并在 48 或 72 小时后继续增加，甚至在 YP-STAT1 浓度恢复到基础水平很久之后。与其作为转录因子的活性一致，在 IFN 处理之前，大多数 U-STAT1 存在于这些细胞的细胞核中，并且在 IFN 处理后 48 小时，细胞核中的比例增加。我们得出的结论是，响应 IFN 而积累的核 U-STAT1 独立于 YP-STAT1 维持或增加了 IFN 诱导基因子集的表达，并且许多诱导蛋白参与免疫调节。
In normal human cells treated with interferons (IFNs), the concentration of tyrosine-phosphorylated STAT1 (YP-STAT1), which drives the expression of a large number of genes, increases quickly but then decreases over a period of several hours. Because the STAT1 gene is activated by YP-STAT1, IFNs stimulate a large increase in the concentration of unphosphorylated STAT1 (U-STAT1) that persists for several days. To test the significance of high U-STAT1 expression, we increased its concentration exogenously in the absence of IFN treatment. In response, the expression of many immune regulatory genes ( e. g., IFI27, IFI44, OAS, and BST2) was increased. In human fibroblasts or mammary epithelial cells treated with low concentrations of IFN-beta or IFN-gamma, the expression of the same genes increased after 6 h and continued to increase after 48 or 72 h, long after the concentration of YP-STAT1 had returned to basal levels. Consistent with its activity as a transcription factor, most U-STAT1 was present in the nuclei of these cells before IFN treatment, and the fraction in nuclei increased 48 h after treatment with IFN. We conclude that the nuclear U-STAT1 that accumulates in response to IFNs maintains or increases the expression of a subset of IFN-induced genes independently of YP-STAT1, and that many of the induced proteins are involved in immune regulation.