Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells.
Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells.
复制标题
羊毛甾醇合酶调节人支气管上皮细胞中的人鼻病毒复制。
DOI：
10.1165/rcmb.2017-0438oc
复制
发表时间：
2018
影响因子：
6.4
通讯作者：
McCrae C
中科院分区：
文献类型：
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作者：
McCrae C
人鼻病毒（RV）感染是哮喘和慢性阻塞性肺病恶化的重要危险因素。因此，在这些患者中预防RV感染的方法将带来显著的益处。通过RNA干扰文库筛选，我们确定了羊毛甾醇合成酶（LSS），胆固醇生物合成途径的一个组成部分，作为一种新的调节RV复制在原代正常人支气管上皮细胞。选择性敲低LSSmRNA抑制RV 2在正常人支气管上皮细胞中的复制。LSS的小分子抑制剂以浓度依赖性方式模拟LSSmRNA敲低的作用。我们进一步证明，抗病毒作用不依赖于总细胞胆固醇的减少，但需要与LSS抑制剂预孵育24小时。所用LSS抑制剂的抗病毒效力的等级顺序与LSS抑制效力一致;然而，与LSS酶效力相比，所有化合物均显示出显著更高的抗RV效力。我们发现LSS抑制导致24（S），25环氧胆固醇的诱导，24（S），25环氧胆固醇是固醇途径的重要调节剂。我们还证明了LSS抑制导致先天抗病毒防御蛋白IFN-β表达的显著增加。我们发现LSS是RV复制和先天性抗病毒免疫的一种新的调节剂，并通过诱导24（S），25环氧胆固醇确定了这种作用的潜在分子机制。因此，抑制LSS可能是预防RV诱导的急性加重的新的治疗靶点。
Human rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. Selective knock down ofLSSmRNA with short interfering RNA inhibited RV2 replication in normal human bronchial epithelial cells. Small molecule inhibitors of LSS mimicked the effect ofLSSmRNA knockdown in a concentration-dependent manner. We further demonstrated that the antiviral effect is not dependent on a reduction in total cellular cholesterol but requires a 24-hour preincubation with the LSS inhibitor. The rank order of antiviral potency of the LSS inhibitors used was consistent with LSS inhibition potency; however, all compounds showed remarkably higher potency against RV compared with the LSS enzyme potency. We showed that LSS inhibition led to an induction of 24(S),25 epoxycholesterol, an important regulator of the sterol pathway. We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-β. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.