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

• DOI: 10.1128/mbio.03358-23
• Publication Date: 2024-02-02T05:00:24Z
• Authors: 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
• Keywords: Coronavirus; Bystander effect; Infectivity; CD63; Angiotensin-converting enzyme 2; Exosome

ABSTRACT 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 (ACE2)-containing exosomes (ACE2-exos) superior antiviral efficacies, especially in response to emerging variants. However, mechanisms how virus counteracts host regulates ACE2-exos remain unclear. Here, we identified SARS-CoV-2 nonstructural protein 6 (NSP6) inhibits production by affecting level ACE2 as well tetraspanin-CD63 is key factor for exosome biogenesis. We further found stability CD63 maintained deubiquitination proteasome 26S subunit, non-ATPase 12 (PSMD12). NSP6 interacts with PSMD12 its function, consequently promoting degradation ACE2. As result, diminishes efficacy facilitates infect healthy bystander cells. Overall, our study provides valuable target discovery promising drugs treatment disease 2019. IMPORTANCE outbreak 2019 (COVID-19) vaccines antibodies declined rapid mutants. Angiotensin-converting 2-containing therapy exhibits broad neutralizing activity, could be used against various viral mutations. here revealed inhibited ACE2-exos, thereby infection adjacent identification new blocking depends on fully understanding virus-host interaction networks. sheds light mechanism resists defenses, would facilitate design ACE2-exos-based therapeutics COVID-19.