Antalis T M, La Linn M, Donnan K, Mateo L, Gardner J, Dickinson J L, Buttigieg K, Suhrbier A
Queensland Cancer Fund Experimental Oncology Unit, The Queensland Institute of Medical Research, Brisbane 4029, Australia.
J Exp Med. 1998 Jun 1;187(11):1799-811. doi: 10.1084/jem.187.11.1799.
The serine proteinase inhibitor (serpin) plasminogen activator inhibitor type 2 (PAI-2) is well characterized as an inhibitor of extracellular urokinase-type plasminogen activator. Here we show that intracellular, but not extracellular, PAI-2 protected cells from the rapid cytopathic effects of alphavirus infection. This protection did not appear to be related to an effect on apoptosis but was associated with a PAI-2-mediated induction of constitutive low-level interferon (IFN)-alpha/beta production and IFN-stimulated gene factor 3 (ISGF3) activation, which primed the cells for rapid induction of antiviral genes. This primed phenotype was associated with a rapid development of resistance to infection by the PAI-2 transfected cells and the establishment of a persistent productive infection. PAI-2 was also induced in macrophages in response to viral RNA suggesting that PAI-2 is a virus response gene. These observations, together with the recently demonstrated PAI-2-mediated inhibition of tumor necrosis factor-alpha induced apoptosis, (a) illustrate that PAI-2 has an additional and distinct function as an intracellular regulator of signal transduction pathway(s) and (b) demonstrate a novel activity for a eukaryotic serpin.
丝氨酸蛋白酶抑制剂（serpin）纤溶酶原激活物抑制剂2型（PAI - 2）作为细胞外尿激酶型纤溶酶原激活物的抑制剂已被充分表征。在此我们表明，细胞内而非细胞外的PAI - 2可保护细胞免受甲病毒感染的快速细胞病变效应。这种保护作用似乎与对细胞凋亡的影响无关，而是与PAI - 2介导的组成型低水平干扰素（IFN）-α/β产生的诱导以及IFN刺激基因因子3（ISGF3）的激活有关，这使细胞能够快速诱导抗病毒基因。这种预激活的表型与PAI - 2转染细胞对感染的抗性快速发展以及持续性生产性感染的建立有关。病毒RNA可诱导巨噬细胞产生PAI - 2，这表明PAI - 2是一种病毒反应基因。这些观察结果，连同最近证明的PAI - 2介导的对肿瘤坏死因子-α诱导的细胞凋亡的抑制作用，（a）说明PAI - 2作为信号转导途径的细胞内调节剂具有额外且独特的功能，（b）证明了真核丝氨酸蛋白酶抑制剂的一种新活性。
