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
Affiliations
Xi Lv
School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
Ran Chen
Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
Taizhen Liang
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong, China
Haojie Peng
Department of Breast Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Qiannan Fang
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Shiqi Xiao
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong, China
Sen Liu
School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
Meilin Hu
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong, China
Fei Yu
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Lixue Cao
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Yiwen Zhang
Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
Ting Pan
Center for Infection and Immunity Studies, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China
Zhihui Xi
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Yao Ding
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Linyuan Feng
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Tao Zeng
Department of Breast Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
Wenjing Huang
Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Hui Zhang
School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
Xiancai Ma
School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
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 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.
