Harada H, Matsumoto M, Sato M, Kashiwazaki Y, Kimura T, Kitagawa M, Yokochi T, Tan R S, Takasugi T, Kadokawa Y, Schindler C, Schreiber R D, Noguchi S, Taniguchi T
Department of Immunology, Faculty of Medicine, University of Tokyo, Hongo, Japan.
Genes Cells. 1996 Nov;1(11):995-1005. doi: 10.1046/j.1365-2443.1996.870287.x.
Efficient production of interferons (IFNs) in virally infected cells is an essential aspect of the host defence. The transcription factor complex ISGF3 (IFN-stimulated gene factor 3) was originally identified as a critical mediator of the IFN signal; it is formed upon IFN receptor (IFNR) stimulation and binds to ISREs (IFN-stimulated response elements) to activate IFN-inducible genes. It has recently been shown that the DNA binding component of ISGF3, p48 (ISGF3gamma) also binds to virus-inducible elements in the IFN-alpha/beta genes, suggesting a potential new role of p48 in IFN production.
Primary cells from mice with a targeted disruption of the p48 gene show severe defects in virus-induced IFN-alpha/beta gene expression. A similar defect was also observed in cells lacking type I IFNR or Stat1, further demonstrating the role of IFN signalling in the induction of these IFN genes. ISGF3 in fact binds to the virus-inducible elements within the IFN-alpha/beta promoters. We also provide evidence showing that these elements are additionally controlled by an unidentified factor(s) which presumably triggers the primary phase of IFN gene induction.
Our results demonstrate that the IFN signal transducing complex ISGF3 plays a crucial role in IFN production and suggest that ISGF3 may participate directly in the activation of IFN-alpha/beta promoters. This dual function of ISGF3 may insure the efficient operation of this cytokine system in the host defence.
在病毒感染的细胞中高效产生干扰素（IFN）是宿主防御的一个重要方面。转录因子复合物ISGF3（IFN刺激基因因子3）最初被鉴定为IFN信号的关键介导因子；它在IFN受体（IFNR）受到刺激时形成，并与ISREs（IFN刺激反应元件）结合以激活IFN诱导基因。最近有研究表明，ISGF3的DNA结合成分p48（ISGF3γ）也与IFN-α/β基因中的病毒诱导元件结合，这表明p48在IFN产生中可能具有新的潜在作用。
来自p48基因靶向破坏小鼠的原代细胞在病毒诱导的IFN-α/β基因表达中表现出严重缺陷。在缺乏I型IFNR或Stat1的细胞中也观察到类似缺陷，进一步证明了IFN信号在这些IFN基因诱导中的作用。事实上，ISGF3与IFN-α/β启动子内的病毒诱导元件结合。我们还提供证据表明，这些元件还受到一个未确定因子的额外控制，该因子可能触发IFN基因诱导的初级阶段。
我们的结果表明，IFN信号转导复合物ISGF3在IFN产生中起关键作用，并表明ISGF3可能直接参与IFN-α/β启动子的激活。ISGF3的这种双重功能可能确保该细胞因子系统在宿主防御中的有效运作。
