下调和上调
生物
基因敲除
血管紧张素转化酶2
冠状病毒
溶酶体
网格蛋白
细胞生物学
免疫学
受体
细胞培养
内吞作用
病毒学
酶
2019年冠状病毒病(COVID-19)
医学
内科学
生物化学
基因
传染病(医学专业)
疾病
遗传学
作者
Yi Lu,Qingwei Zhu,Douglas M Fox,Carol Gao,Sarah A Stanley,Kunxin Luo
标识
DOI:10.1091/mbc.e22-02-0045
摘要
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its Spike (S) glycoprotein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry. ACE2 is a critical negative regulator of the Renin-Angiotensin system and plays a protective role in preventing tissue injury. Expression of ACE2 has been shown to decrease upon infection by SARS-CoV. However, whether SARS-CoV-2 downregulates ACE2, as well as the underlying mechanism and biological impact of this downregulation have not been well defined. Here we show that the SARS-CoV-2 infection downregulates ACE2 in vivo in an animal model, and in cultured cells in vitro, SARS-CoV-2 S protein downregulates ACE2 by inducing clathrin- and AP2-dependent endocytosis, leading to its degradation in the lysosome. SARS-CoV-2 S-treated cells and ACE2 knockdown cells exhibit similar alterations in downstream gene expression, with a pattern indicative of activated cytokine signaling that is associated with respiratory distress and inflammatory diseases often observed in COVID-19 patients. Finally, we have identified a soluble ACE2 fragment with a stronger binding to SARS-CoV-2 S that can efficiently block ACE2 downregulation and viral infection. Thus, our study suggests that ACE2 downregulation represents an important mechanism underlying SARS-CoV-2-associated pathology, and blocking this process could be a promising therapeutic strategy.
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