Holland K A, Owczarek C M, Hwang S Y, Tymms M J, Constantinescu S N, Pfeffer L M, Kola I, Hertzog P J
Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia.
J Biol Chem. 1997 Aug 22;272(34):21045-51. doi: 10.1074/jbc.272.34.21045.
The type I interferons (IFNs) are a family of cytokines, comprising at least 17 subtypes, which exert pleiotropic actions by interaction with a multi-component cell surface receptor and at least one well characterized signal transduction pathway involving JAK/STAT (Janus kinase/signal transducer and activator of transcription) proteins. In a previous report, we showed that a signaling factor, encoded by a gene located on the distal portion of chromosome 21, distinct from the IFNAR-1 receptor, was necessary for 2'-5'-oligoadenylate synthetase activity and antiviral responses, but not for high affinity ligand binding. In the present studies using hybrid Chinese hamster ovary cell lines containing portions of human chromosome 21, we show that the type I IFN signaling molecule, designated herein as ISF21, is distinct from the second receptor component, IFNAR-2, which is expressed in signaling and non-signaling cell lines. The location of the gene encoding ISF21 is narrowed to a region between the 10;21 and the r21 breakpoints, importantly eliminating the Mx gene located at 21q22.3 (the product of which is involved in IFN-induced antiviral responses) as a candidate for the signaling factor. To characterize the action of this factor in the type I IFN signaling pathway, we show that it acts independently of receptor down-regulation following ligand binding, both of which occur equally in the presence or absence of the factor. In addition, we demonstrate that ISF21 is necessary for transcriptional activation of 2'-5'-oligoadenylate synthetase, 6-16, and guanylate-binding protein gene promoter reporter constructs, which are mediated by several signaling pathways. ISF21 represents a novel factor as the localization to chromosome 21, and the data presented in this study exclude any of the known type I IFN signal-transducing molecules.
I型干扰素（IFN）是一类细胞因子，至少由17个亚型组成，它们通过与多组分细胞表面受体以及至少一条涉及JAK/STAT（Janus激酶/信号转导子和转录激活子）蛋白的特征明确的信号转导途径相互作用，发挥多效性作用。在之前的一份报告中，我们表明，由位于21号染色体远端的一个基因编码的一种信号因子，不同于IFNAR-1受体，它对于2'-5'-寡腺苷酸合成酶活性和抗病毒反应是必需的，但对于高亲和力配体结合则不是必需的。在本研究中，我们使用含有部分人类21号染色体的中国仓鼠卵巢杂交细胞系，表明I型IFN信号分子（本文命名为ISF21）不同于第二种受体组分IFNAR-2，后者在信号转导和非信号转导细胞系中均有表达。编码ISF21的基因的位置被缩小到10;21和r21断点之间的一个区域，重要的是排除了位于21q22.3的Mx基因（其产物参与IFN诱导的抗病毒反应）作为该信号因子的候选基因。为了表征该因子在I型IFN信号通路中的作用，我们表明它在配体结合后独立于受体下调发挥作用，无论有无该因子，两者均同等发生。此外，我们证明ISF21对于由几种信号通路介导的2'-5'-寡腺苷酸合成酶、6-16和鸟苷酸结合蛋白基因启动子报告构建体的转录激活是必需的。ISF21作为定位于21号染色体的一种新因子，本研究提供的数据排除了任何已知的I型IFN信号转导分子。
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