USP18 establishes the transcriptional and anti-proliferative interferon α/β differential
USP18 establishes the transcriptional and anti-proliferative interferon α/β differential
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DOI：
10.1042/bj20120541
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发表时间：
2012-09-15
影响因子：
4.1
通讯作者：
Pellegrini, Sandra
中科院分区：
文献类型：
--
作者：
Francois-Newton, Veronique;Livingstone, Mark;Pellegrini, Sandra
I型IFN（干扰素）是病原体诱导的免疫调节细胞因子，其通过与共同的细胞表面受体结合而发挥抗病毒和抗增殖活性。在17种人IFN亚型中。与IFN α 2相比，IFN β以特别高的亲和力结合IFNAR（IFN α受体）1/IFNAR 2受体链，并且在选择生物活性（例如抗增殖和促凋亡）方面特别有效。然而，没有分子基础已被归因于这种差异的行动，因为这两个配体是等效的立即早期信号事件。在本研究中，我们报告说，IFN β诱导Stat（信号转导和转录激活因子）磷酸化和转录激活的ISGs（干扰素刺激的基因），包括两个基因与促凋亡功能，为一个相当长的时间框架比IFN α 2。我们表明，α 2/β反应的多样化逐渐建立在受体水平上，作为积累USP 18（泛素特异性蛋白酶18）的结果，USP 18本身是一种ISG，它通过利用IFN α 2与受体结合的弱点发挥其负反馈作用。这代表了一种新型的信号调节，使IFN α和IFN β的生物潜力多样化。
Type I IFNs (interferons) are pathogen-induced immunoregulatory cytokines that exert anti-viral and anti-proliferative activities through binding to a common cell-surface receptor. Among the 17 human IFN subtypes. IFN beta binds the IFNAR (IFN alpha receptor) 1/IFNAR2 receptor chains with particularly high affinity and is especially potent in select bioactivities (e.g. anti-proliferative and pro-apoptotic) when compared with IFN alpha 2. However, no molecular basis has been ascribed to this differential action, since the two ligands are equipotent in immediate early signalling events. In the present study we report that IFN beta induces Stat (signal transducer and activator of transcription) phosphorylation and transcriptional activation of ISGs (interferon-stimulated genes), including two genes with pro-apoptotic functions, for a considerably longer time frame than does IFN alpha 2. We show that the diversification of alpha 2/beta responses progressively builds up at the receptor level as a result of accumulating USP18 (ubiquitin-specific protease 18), itself an ISG, which exerts its negative feedback action by taking advantage of the weakness of IFN alpha 2 binding to the receptor. This represents a novel type of signalling regulation that diversifies the biological potential of IFNs alpha and beta.