Li Wen, Hofer Markus J, Songkhunawej Pattama, Jung So Ri, Hancock Dale, Denyer Gareth, Campbell Iain L
From the School of Molecular Bioscience.
Bosch Institute, and.
J Biol Chem. 2017 Apr 7;292(14):5845-5859. doi: 10.1074/jbc.M116.756510. Epub 2017 Feb 17.
Type I interferons (IFN-I) are critical in antimicrobial and antitumor defense. Although IFN-I signal via the interferon-stimulated gene factor 3 (ISGF3) complex consisting of STAT1, STAT2, and IRF9, IFN-I can mediate significant biological effects via ISGF3-independent pathways. For example, the absence of STAT1, STAT2, or IRF9 exacerbates neurological disease in transgenic mice with CNS production of IFN-I. Here we determined the role of IFN-I-driven, ISGF3-independent signaling in regulating global gene expression in STAT1-, STAT2-, or IRF9-deficient murine mixed glial cell cultures (MGCs). Compared with WT, the expression of IFN-α-stimulated genes (ISGs) was reduced in number and magnitude in MGCs that lacked STAT1, STAT2, or IRF9. There were significantly fewer ISGs in the absence of STAT1 or STAT2 in the absence of IRF9. The majority of ISGs regulated in the STAT1-, STAT2-, or IRF9-deficient MGCs individually were shared with WT. However, only a minor number of ISGs were common to WT and STAT1-, STAT2-, and IRF9-deficient MGCs. Whereas signal pathway activation in response to IFN-α was rapid and transient in WT MGCs, this was delayed and prolonged and correlated with increased numbers of ISGs expressed at 12 h 4 h of IFN-α exposure in all three IFN-I signaling-deficient MGCs. In conclusion, 1) IFN-I can mediate ISG expression in MGCs via ISGF3-independent signaling pathways but with reduced efficiency, with delayed and prolonged kinetics, and is more dependent on STAT1 and STAT2 than IRF9; and 2) signaling pathways not involving STAT1, STAT2, or IRF9 play a minor role only in mediating ISG expression in MGCs.
I型干扰素(IFN-I)在抗菌和抗肿瘤防御中至关重要。尽管IFN-I通过由STAT1、STAT2和IRF9组成的干扰素刺激基因因子3(ISGF3)复合物发出信号,但IFN-I可通过不依赖ISGF3的途径介导显著的生物学效应。例如,在中枢神经系统产生IFN-I的转基因小鼠中,STAT1、STAT2或IRF9的缺失会加剧神经疾病。在此,我们确定了IFN-I驱动的、不依赖ISGF3的信号传导在调节STAT1、STAT2或IRF9缺陷的小鼠混合神经胶质细胞培养物(MGC)中全局基因表达的作用。与野生型(WT)相比,缺乏STAT1、STAT2或IRF9的MGC中,IFN-α刺激基因(ISG)的表达数量和幅度均降低。在缺乏IRF9的情况下,缺乏STAT1或STAT2时的ISG明显更少。在STAT1、STAT2或IRF9缺陷的MGC中分别受调节的大多数ISG与WT共有。然而,WT与STAT1、STAT2和IRF9缺陷的MGC中只有少数ISG是共同的。在WT MGC中,对IFN-α的信号通路激活迅速且短暂,而在所有三种IFN-I信号缺陷的MGC中,这种激活延迟且延长,并与IFN-α暴露后4小时和12小时表达的ISG数量增加相关。总之,1)IFN-I可通过不依赖ISGF3的信号通路介导MGC中的ISG表达,但效率降低,动力学延迟且延长,并且比IRF9更依赖于STAT1和STAT2;2)不涉及STAT1、STAT2或IRF9的信号通路在介导MGC中的ISG表达中仅起次要作用。