Yang Zhe, Zhang Qi, Wu Xiaoqing, Hao Siyuan, Hao Xinbao, Jones Elizabeth, Zhang Yuxia, Qiu Jianming, Xu Liang
Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA.
Higuchi Biosciences Center, The University of Kansas, Lawrence, KS 66045, USA.
Biomedicines. 2023 Jul 18;11(7):2019. doi: 10.3390/biomedicines11072019.
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic, and the search for effective treatments has been limited. Furthermore, the rapid mutations of SARS-CoV-2 have posed challenges to existing vaccines and neutralizing antibodies, as they struggle to keep up with the increased viral transmissibility and immune evasion. However, there is hope in targeting the CD147-spike protein, which serves as an alternative point for the entry of SARS-CoV-2 into host cells. This protein has emerged as a promising therapeutic target for the development of drugs against COVID-19. Here, we demonstrate that the RNA-binding protein Human-antigen R (HuR) plays a crucial role in the post-transcriptional regulation of CD147 by directly binding to its 3'-untranslated region (UTR). We observed a decrease in CD147 levels across multiple cell lines upon HuR depletion. Furthermore, we identified that niclosamide can reduce CD147 by lowering the cytoplasmic translocation of HuR and reducing CD147 glycosylation. Moreover, our investigation revealed that SARS-CoV-2 infection induces an upregulation of CD147 in ACE2-expressing A549 cells, which can be effectively neutralized by niclosamide in a dose-dependent manner. Overall, our study unveils a novel regulatory mechanism of regulating CD147 through HuR and suggests niclosamide as a promising therapeutic option against COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的爆发导致了全球2019冠状病毒病（COVID-19）大流行，而有效治疗方法的探索一直很有限。此外，SARS-CoV-2的快速突变给现有疫苗和中和抗体带来了挑战，因为它们难以跟上病毒传播性增加和免疫逃逸的速度。然而，靶向CD147-刺突蛋白有希望，它是SARS-CoV-2进入宿主细胞的另一个切入点。这种蛋白已成为开发抗COVID-19药物的一个有前景的治疗靶点。在这里，我们证明RNA结合蛋白人抗原R（HuR）通过直接结合CD147的3'-非翻译区（UTR）在其转录后调控中起关键作用。我们观察到在多个细胞系中HuR缺失后CD147水平下降。此外，我们发现氯硝柳胺可以通过降低HuR的细胞质转位和减少CD147糖基化来降低CD147。而且，我们的研究表明SARS-CoV-2感染会诱导表达ACE2的A549细胞中CD147上调，氯硝柳胺可以以剂量依赖的方式有效中和这种上调。总体而言，我们的研究揭示了通过HuR调节CD147的一种新的调控机制，并表明氯硝柳胺是一种有前景的抗COVID-19治疗选择。
