Dysregulation of the ubiquitin-proteasome system by curcumin suppresses coxsackievirus B3 replication
Dysregulation of the ubiquitin-proteasome system by curcumin suppresses coxsackievirus B3 replication
复制标题
DOI：
10.1128/jvi.02028-06
复制
发表时间：
2007-04-01
影响因子：
5.4
通讯作者：
Luo, Honglin
中科院分区：
文献类型：
--
作者：
Si, Xiaoning;Wang, Yahong;Luo, Honglin
姜黄素（二阿魏酰甲烷），一种从香料姜黄中提取的天然多酚化合物，已被报道具有抗炎，抗氧化和抗增殖特性，通过调节多种细胞机制。在各种细胞类型中，它抑制几种细胞内信号传导途径，包括促分裂原活化蛋白激酶（MAPK）、酪蛋白激酶II（CKII）和COP 9信号体（CSN）。最近还证明，暴露于姜黄素导致泛素-蛋白酶体系统（UPS）的失调。柯萨奇病毒感染与各种疾病有关，包括心肌炎和扩张型心肌病。在寻找新的抗柯萨奇病毒的抗病毒药物时，我们发现姜黄素治疗可显著降低病毒RNA表达、蛋白质合成和病毒滴度，并保护细胞免受病毒诱导的细胞病变效应和凋亡。我们进一步证明，姜黄素减少病毒感染不太可能是由于抑制CVB 3与其受体结合或CVB 3诱导的MAPKs活化。此外，CKII和Jab 1，CSN的一个组成部分，基因沉默的小干扰RNA，并没有抑制柯萨奇病毒的复制，这表明姜黄素的抗病毒作用是独立于这些途径。最后，我们发现姜黄素治疗降低了20 S蛋白酶体蛋白水解活性和细胞去泛素化活性，导致泛素化蛋白的积累增加和游离泛素的蛋白水平降低。我们最近发现，UPS介导的蛋白质降解和/或修饰在柯萨奇病毒复制的调节中起着关键作用。因此，我们的研究结果表明姜黄素的重要抗病毒作用，其中它通过UPS的失调有效地抑制柯萨奇病毒复制。
Curcumin (diferuloylmethane), a natural polyphenolic compound extracted from the spice turmeric, has been reported to have anti-inflammatory, antioxidant, and antiproliferative properties by modulating multiple cellular machineries. It inhibits several intracellular signaling pathways, including the mitogen-activated protein kinases (MAPKs), casein kinase II (CKII), and the COP9 signalosome (CSN), in various cell types. It has also been recently demonstrated that exposure to curcumin leads to the dysregulation of the ubiquitin-proteasome system (UPS). Coxsackievirus infection is associated with various diseases, including myocarditis and dilated cardiomyopathy. In searching for new antiviral agents against coxsackievirus, we found that treatment with curcumin significantly reduced viral RNA expression, protein synthesis, and virus titer and protected cells from virus-induced cytopathic effect and apoptosis. We further demonstrated that reduction of viral infection by curcumin was unlikely due to inhibition of CVB3 binding to its receptors or CVB3-induced activation of MAPKs. Moreover, gene silencing of CKII and Jab1, a component of CSN, by small interfering RNAs did not inhibit the replication of coxsackievirus, suggesting that the antiviral action of curcumin is independent of these pathways. Finally, we showed that curcumin treatment reduced both the 20S proteasome proteolytic activities and the cellular deubiquitinating activities, leading to increased accumulation of ubiquitinated proteins and decreased protein levels of free ubiquitin. We have recently demonstrated that the UPS-mediated protein degradation and/or modification plays a critical role in the regulation of coxsackievirus replication. Thus, our results suggest an important antiviral effect of curcumin wherein it potently inhibits coxsackievirus replication through dysregulation of the UPS.