All four Sendai virus C proteins bind Stat1, but only the larger forms also induce its mono-ubiquitination and degradation
All four Sendai virus C proteins bind Stat1, but only the larger forms also induce its mono-ubiquitination and degradation
复制标题
DOI：
10.1006/viro.2001.1342
复制
发表时间：
2002-04-10
期刊：
影响因子：
3.7
通讯作者：
Kolakofsky, D
中科院分区：
文献类型：
--
作者：
Garcin, D;Marq, JB;Kolakofsky, D
仙台病毒感染强烈诱导干扰素 (IFN) 产生，最近被证明可以通过 Jak/Stat 途径阻断后续的 IFN 信号传导。SeV 的抗 IFN 活性归因于其“C”蛋白，这是一组嵌套的四种蛋白（C、C、Y1、Y2），在对抗先天免疫反应中执行一系列嵌套功能。我们之前报道过所有四种 C 蛋白都与 Stat1 相互作用，以阻止通过 Jak/Stat 途径的 IFN 信号传导。然而，只有较长的 C 蛋白才能降低 Stat1 水平，并阻止 IFN 在具有 IFN 活性的小鼠细胞中诱导抗病毒 (VSV) 状态或细胞凋亡。在这里，我们研究了各种 C 蛋白差异影响宿主抗病毒防御的机制。发现所有四种 C 蛋白在细胞培养物感染期间与 Stat1 物理关联。以及在没有其他病毒基因产物的情况下的体外实验（如免疫共沉淀所证明）。此外，无效突变体 (C-F170S) 无法结合 Stat1，表明这种相互作用具有生理相关性。我们还表明，蛋白酶体抑制剂 MG132 可以阻止 C 蛋白诱导的小鼠细胞中抗病毒 (VSV) 状态的解体；因此，Stat1 的更新与 C 蛋白介导的抗病毒 (VSV) 状态的对抗相关。 C 蛋白诱导的 Stat1 不稳定性伴随着单泛素化 Stat1 水平的明显增加，这是蛋白质降解的一个意想不到的标志。最后，我们表明，具有突变 C 蛋白但具有野生型 Y 蛋白（CDelta10-15，即使它们的 C 蛋白结合 Stat1 并阻止其活性，也不会抵消 MEF 的内源抗病毒（VSV）状态）的 rSeV 也无法降低大量 Stat1 水平或增加泛素化 Statl 的水平。 (C) 2002 年爱思唯尔科学（美国）。
Sendai virus infection strongly induces interferon (IFN) production and has recently been shown to interdict the subsequent IFN signaling through the Jak/Stat pathway This anti-IFN activity of SeV is due to its "C" proteins, a nested set of four proteins (C, C, Y1, Y2) that carry out a nested set of functions in countering the innate immune response. We previously reported that all four C proteins interact with Stat1 to prevent IFN signaling through the Jak/Stat pathway. Nevertheless, only the longer C proteins reduced Stat1 levels and prevented IFN from inducing an antiviral (VSV) state, or apoptosis, in IFN-competent murine cells. Here, we investigate the mechanism by which the various C proteins differentially affect the host antiviral defenses All four C proteins were found to physically associate with Stat1 during cell culture infections. and in vitro in the absence of other viral gene products (as evidenced by co-immunoprecipitation). In addition, the inability of a null mutant (C-F170S) to bind Stat1 suggests that this interaction is physiologically relevant. We have also shown that the proteasomal inhibitor MG132 can prevent the C protein-induced dismantling of the antiviral (VSV) state in murine cells; thus, the turnover of Stat1 correlates with the C protein-mediated counteraction of the antiviral (VSV) state. The C protein-induced instability of Stat1 was accompanied by a clear increase in the level of mono-ubiquinated Stat1, an unexpected hallmark of protein degradation. Finally, we show that a rSeV with mutant C proteins but wild-type Y proteins (CDelta10-15, that does not counteract the endogenous antiviral (VSV) state of MEFs even though their C proteins bind Stat1 and prevent its activity) is also unable to decrease bulk Stat1 levels or to increase the level of ubiquinated Statl. (C) 2002 Elsevier Science (USA).