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TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction
Hataf Khan1, Helena Winstone1, Jose M Jimenez-Guardeño1
1Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.
Human nuclear receptor coactivator 7 (NCOA7) restricts SARS-CoV-2 entry by acidifying endosomes. This interferon-stimulated gene
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Interferons (IFNs) are crucial for antiviral immunity against SARS-CoV-2.
- The specific interferon-stimulated genes (ISGs) that inhibit SARS-CoV-2 are not fully understood.
- NCOA7 is an IFN-inducible protein involved in endosomal acidification.
Purpose of the Study:
- To investigate the role of NCOA7 in restricting SARS-CoV-2 infection.
- To determine the mechanisms by which NCOA7 inhibits viral entry.
- To explore NCOA7's effect on other coronaviruses and the influence of viral factors.
Main Methods:
- Ectopic expression of NCOA7 in lung epithelial cells.
- Gene knockout of NCOA7.
- Pseudotyped virus infection assays (SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E, HCoV-NL63).
- Manipulation of viral factors (TMPRSS2 overexpression, Spike furin cleavage site removal).
Main Results:
- NCOA7 inhibits infection by SARS-CoV-2 and other coronavirus pseudotyped viruses.
- NCOA7 functions by promoting endo-lysosomal acidification and protease activity.
- SARS-CoV-2 variants with TMPRSS2 overexpression or lacking furin cleavage site show reduced sensitivity to NCOA7.
- Furin cleavage sensitizes SARS-CoV-2 Spike to NCOA7-mediated endosomal restriction.
Conclusions:
- NCOA7 acts as a broad-spectrum antiviral effector against coronaviruses.
- Furin cleavage of SARS-CoV-2 Spike enhances its susceptibility to NCOA7-induced endosomal restriction.
- Viruses may evolve to evade NCOA7-mediated antiviral defenses by utilizing alternative entry pathways or modifying Spike protein.
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