P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation.
P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation.
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DOI：
10.1038/s41392-023-01631-0
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发表时间：
2023-10-09
影响因子：
39.3
通讯作者：
Zhang, Yuxia
中科院分区：
文献类型：
--
作者：
Liu, Ming;Lu, Bingtai;Li, Yue;Yuan, Shuofeng;Zhuang, Zhen;Li, Guangyu;Wang, Dong;Ma, Liuheyi;Zhu, Jianheng;Zhao, Jinglu;Chan, Chris Chung-Sing;Poon, Vincent Kwok-Man;Chik, Kenn Ka-Heng;Zhao, Zhiyao;Xian, Huifang;Zhao, Jingxian;Zhao, Jincun;Chan, Jasper Fuk-Woo;Zhang, Yuxia
严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）是2019年冠状病毒病（COVID-19）的病原体，对全球医疗保健系统和经济产生了重大影响。新病毒株的不断出现对有效抗病毒药物的开发提出了重大挑战。具有广谱抗病毒活性的策略是控制SARS-CoV-2感染的理想策略。ACE 2是一种含有血管紧张素的酶，可防止肾素血管紧张素系统过度活化，是SARS-CoV-2的受体。ACE 2与刺突蛋白相互作用，并促进病毒附着和进入宿主细胞。然而，SARS-CoV-2感染也促进ACE 2降解。恢复ACE 2表面表达是否对SARS-CoV-2感染有影响尚未确定。在这里，我们表明，ACE 2穗复合物是内吞和降解的方式，依赖于网格蛋白介导的内吞作用和PAK 1介导的细胞骨架重排通过自噬。相反，游离的细胞刺突蛋白以溶酶体依赖性方式被选择性地切割成S1和S2亚基。重要的是，我们发现泛PAK抑制剂FRAX-486恢复ACE 2表面表达，并抑制不同SARS-CoV-2菌株的感染。与未处理的仓鼠相比，FRAX-486处理的叙利亚仓鼠表现出显著降低的肺病毒载量和减轻的肺部炎症。总之，我们的研究结果已经确定了调节病毒进入的新途径，以及用于控制新出现的SARS-CoV-2感染菌株的治疗靶点和候选化合物。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has had a significant impact on healthcare systems and economies worldwide. The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents. Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection. ACE2, an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system, is the receptor for SARS-CoV-2. ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells. Yet, SARS-CoV-2 infection also promotes ACE2 degradation. Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined. Here, we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement. In contrast, free cellular spike protein is selectively cleaved into S1 and S2 subunits in a lysosomal-dependent manner. Importantly, we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains. FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters. In summary, our findings have identified novel pathways regulating viral entry, as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.
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影响因子：
16.6
作者：
Chen, Lin-Lei;Abdullah, Syed Muhammad Umer;Chan, Wan-Mui;Chan, Brian Pui-Chun;Ip, Jonathan Daniel;Chu, Allen Wing-Ho;Lu, Lu;Zhang, Xiaojuan;Zhao, Yan;Chuang, Vivien Wai-Man;Au, Albert Ka-Wing;Cheng, Vincent Chi-Chung;Sridhar, Siddharth;Yuen, Kwok-Yung;Hung, Ivan Fan-Ngai;Chan, Kwok-Hung;To, Kelvin Kai-Wang
通讯作者：
To, Kelvin Kai-Wang
DOI：
10.1161/atvbaha.112.248559
发表时间：
2012-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Gupte M;Thatcher SE;Boustany-Kari CM;Shoemaker R;Yiannikouris F;Zhang X;Karounos M;Cassis LA
通讯作者：
Cassis LA
影响因子：
13.2
作者：
Chan, Jasper Fuk-Woo;Kok, Kin-Hang;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung
影响因子：
168.9
作者：
Chan, Jasper Fuk-Woo;Yuan, Shuofeng;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung
影响因子：
5.4
作者：
Glowacka, Ilona;Bertram, Stephanie;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan