mBio (Mar 2024)

NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity

  • Xi Lv,
  • Ran Chen,
  • Taizhen Liang,
  • Haojie Peng,
  • Qiannan Fang,
  • Shiqi Xiao,
  • Sen Liu,
  • Meilin Hu,
  • Fei Yu,
  • Lixue Cao,
  • Yiwen Zhang,
  • Ting Pan,
  • Zhihui Xi,
  • Yao Ding,
  • Linyuan Feng,
  • Tao Zeng,
  • Wenjing Huang,
  • Hui Zhang,
  • Xiancai Ma

DOI
https://doi.org/10.1128/mbio.03358-23
Journal volume & issue
Vol. 15, no. 3

Abstract

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ABSTRACTThe 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.

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