P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation
© 2023. West China Hospital, Sichuan University..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Signal transduction and targeted therapy - 8(2023), 1 vom: 09. Okt., Seite 385 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Ming [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.11.2023 Date Revised 10.01.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41392-023-01631-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363005838 |
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| 500 | |a Date Revised 10.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. West China Hospital, Sichuan University. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Lu, Bingtai |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Shuofeng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guangyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Liuheyi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Jianheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jinglu |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Chris Chung-Sing |e verfasserin |4 aut | |
| 700 | 1 | |a Poon, Vincent Kwok-Man |e verfasserin |4 aut | |
| 700 | 1 | |a Chik, Kenn Ka-Heng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Zhiyao |e verfasserin |4 aut | |
| 700 | 1 | |a Xian, Huifang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jingxian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jincun |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Jasper Fuk-Woo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yuxia |e verfasserin |4 aut | |
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