tetano
Editor, Senior Moderator
mBio
. 2024 Feb 2:e0335823.
doi: 10.1128/mbio.03358-23. Online ahead of print. NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity
Xi Lv[SUP] 1 2 [/SUP], Ran Chen[SUP] 3 [/SUP], Taizhen Liang[SUP] 4 [/SUP], Haojie Peng[SUP] 5 [/SUP], Qiannan Fang[SUP] 2 [/SUP], Shiqi Xiao[SUP] 4 [/SUP], Sen Liu[SUP] 1 4 [/SUP], Meilin Hu[SUP] 4 5 [/SUP], Fei Yu[SUP] 2 [/SUP], Lixue Cao[SUP] 2 [/SUP], Yiwen Zhang[SUP] 3 [/SUP], Ting Pan[SUP] 6 [/SUP], Zhihui Xi[SUP] 2 [/SUP], Yao Ding[SUP] 2 [/SUP], Linyuan Feng[SUP] 2 [/SUP], Tao Zeng[SUP] 5 [/SUP], Wenjing Huang[SUP] 2 [/SUP], Hui Zhang[SUP] 1 2 3 [/SUP], Xiancai Ma[SUP] 1 2 4 [/SUP]
Affiliations
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global pandemic, which severely endangers public health. Our and others' works have shown that the angiotensin-converting enzyme 2 (ACE2)-containing exosomes (ACE2-exos) have superior antiviral efficacies, especially in response to emerging variants. However, the mechanisms of how the virus counteracts the host and regulates ACE2-exos remain unclear. Here, we identified that SARS-CoV-2 nonstructural protein 6 (NSP6) inhibits the production of ACE2-exos by affecting the protein level of ACE2 as well as tetraspanin-CD63 which is a key factor for exosome biogenesis. We further found that the protein stability of CD63 and ACE2 is maintained by the deubiquitination of proteasome 26S subunit, non-ATPase 12 (PSMD12). NSP6 interacts with PSMD12 and counteracts its function, consequently promoting the degradation of CD63 and ACE2. As a result, NSP6 diminishes the antiviral efficacy of ACE2-exos and facilitates the virus to infect healthy bystander cells. Overall, our study provides a valuable target for the discovery of promising drugs for the treatment of coronavirus disease 2019.IMPORTANCEThe outbreak of coronavirus disease 2019 (COVID-19) severely endangers global public health. The efficacy of vaccines and antibodies declined with the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants. Angiotensin-converting enzyme 2-containing exosomes (ACE2-exos) therapy exhibits a broad neutralizing activity, which could be used against various viral mutations. Our study here revealed that SARS-CoV-2 nonstructural protein 6 inhibited the production of ACE2-exos, thereby promoting viral infection to the adjacent bystander cells. The identification of a new target for blocking SARS-CoV-2 depends on fully understanding the virus-host interaction networks. Our study sheds light on the mechanism by which the virus resists the host exosome defenses, which would facilitate the study and design of ACE2-exos-based therapeutics for COVID-19.
Keywords: ACE2; CD63; NSP6; PSMD12; SARS-CoV-2; exosomes.
. 2024 Feb 2:e0335823.
doi: 10.1128/mbio.03358-23. Online ahead of print. NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity
Xi Lv[SUP] 1 2 [/SUP], Ran Chen[SUP] 3 [/SUP], Taizhen Liang[SUP] 4 [/SUP], Haojie Peng[SUP] 5 [/SUP], Qiannan Fang[SUP] 2 [/SUP], Shiqi Xiao[SUP] 4 [/SUP], Sen Liu[SUP] 1 4 [/SUP], Meilin Hu[SUP] 4 5 [/SUP], Fei Yu[SUP] 2 [/SUP], Lixue Cao[SUP] 2 [/SUP], Yiwen Zhang[SUP] 3 [/SUP], Ting Pan[SUP] 6 [/SUP], Zhihui Xi[SUP] 2 [/SUP], Yao Ding[SUP] 2 [/SUP], Linyuan Feng[SUP] 2 [/SUP], Tao Zeng[SUP] 5 [/SUP], Wenjing Huang[SUP] 2 [/SUP], Hui Zhang[SUP] 1 2 3 [/SUP], Xiancai Ma[SUP] 1 2 4 [/SUP]
Affiliations
- PMID: 38303107
- DOI: 10.1128/mbio.03358-23
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global pandemic, which severely endangers public health. Our and others' works have shown that the angiotensin-converting enzyme 2 (ACE2)-containing exosomes (ACE2-exos) have superior antiviral efficacies, especially in response to emerging variants. However, the mechanisms of how the virus counteracts the host and regulates ACE2-exos remain unclear. Here, we identified that SARS-CoV-2 nonstructural protein 6 (NSP6) inhibits the production of ACE2-exos by affecting the protein level of ACE2 as well as tetraspanin-CD63 which is a key factor for exosome biogenesis. We further found that the protein stability of CD63 and ACE2 is maintained by the deubiquitination of proteasome 26S subunit, non-ATPase 12 (PSMD12). NSP6 interacts with PSMD12 and counteracts its function, consequently promoting the degradation of CD63 and ACE2. As a result, NSP6 diminishes the antiviral efficacy of ACE2-exos and facilitates the virus to infect healthy bystander cells. Overall, our study provides a valuable target for the discovery of promising drugs for the treatment of coronavirus disease 2019.IMPORTANCEThe outbreak of coronavirus disease 2019 (COVID-19) severely endangers global public health. The efficacy of vaccines and antibodies declined with the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants. Angiotensin-converting enzyme 2-containing exosomes (ACE2-exos) therapy exhibits a broad neutralizing activity, which could be used against various viral mutations. Our study here revealed that SARS-CoV-2 nonstructural protein 6 inhibited the production of ACE2-exos, thereby promoting viral infection to the adjacent bystander cells. The identification of a new target for blocking SARS-CoV-2 depends on fully understanding the virus-host interaction networks. Our study sheds light on the mechanism by which the virus resists the host exosome defenses, which would facilitate the study and design of ACE2-exos-based therapeutics for COVID-19.
Keywords: ACE2; CD63; NSP6; PSMD12; SARS-CoV-2; exosomes.