Malakhova Oxana A, Yan Ming, Malakhov Michael P, Yuan Youzhong, Ritchie Kenneth J, Kim Keun Il, Peterson Luke F, Shuai Ke, Zhang Dong-Er
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Genes Dev. 2003 Feb 15;17(4):455-60. doi: 10.1101/gad.1056303.
ISG15 is one of the most strongly induced genes upon viral infection, type I interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation. Here we report that mice lacking UBP43, a protease that removes ISG15 from ISGylated proteins, are hypersensitive to type I IFN. Most importantly, in UBP43-deficient cells, IFN-beta induces a prolonged Stat1 tyrosine phosphorylation, DNA binding, and IFN-mediated gene activation. Furthermore, restoration of ISG15 conjugation in protein ISGylation-defective K562 cells increases IFN-stimulated promoter activity. These findings identify UBP43 as a novel negative regulator of IFN signaling and suggest the involvement of protein ISGylation in the regulation of the JAK-STAT pathway.
ISG15是病毒感染、I型干扰素(IFN)刺激和脂多糖(LPS)刺激后诱导最强的基因之一。在此我们报告,缺乏UBP43(一种从ISG化蛋白中去除ISG15的蛋白酶)的小鼠对I型干扰素高度敏感。最重要的是,在缺乏UBP43的细胞中,IFN-β诱导Stat1酪氨酸磷酸化、DNA结合以及IFN介导的基因激活延长。此外,在蛋白ISG化缺陷的K562细胞中恢复ISG15缀合可增加IFN刺激的启动子活性。这些发现确定UBP43是IFN信号传导的新型负调节因子,并提示蛋白ISG化参与JAK-STAT途径的调节。