School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
FEBS Lett. 2013 May 21;587(10):1571-8. doi: 10.1016/j.febslet.2013.03.041. Epub 2013 Apr 12.
JAK/STAT signalling is essential for anti-viral immunity, making IFN-α an obvious anti-viral therapeutic. However, many HCV+ patients fail treatment, indicating that the virus blocks successful IFN-α signalling. We found that STAT1 and STAT3 proteins, key components of the IFN-α signalling pathway were reduced in immune cells and hepatocytes from HCV infected patients, and upon HCV expression in Huh7 hepatocytes. However, STAT1 and STAT3 mRNA levels were normal. Mechanistic analysis revealed that in the presence of HCV, STAT3 protein was preferentially ubiquitinated, and degradation was blocked by the proteasomal inhibitor MG132. These findings show that HCV inhibits IFN-α responses in a broad spectrum of cells via proteasomal degradation of JAK/STAT pathway components.
JAK/STAT 信号通路对于抗病毒免疫至关重要，使得 IFN-α成为一种明显的抗病毒治疗药物。然而，许多 HCV+患者的治疗失败，表明该病毒阻止了 IFN-α信号通路的成功激活。我们发现，在 HCV 感染患者的免疫细胞和肝细胞中，以及在 Huh7 肝细胞中 HCV 表达时，IFN-α信号通路的关键组成部分 STAT1 和 STAT3 蛋白减少。然而，STAT1 和 STAT3 的 mRNA 水平正常。机制分析表明，在 HCV 存在的情况下，STAT3 蛋白被优先泛素化，并且蛋白酶体抑制剂 MG132 阻止了其降解。这些发现表明，HCV 通过 JAK/STAT 通路成分的蛋白酶体降解，在广泛的细胞中抑制 IFN-α反应。
