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Production of a SARS-CoV-2 Virus-Like-Particle System to Investigate Viral Life Cycles In Vitro
Published on: June 6, 2025
373
PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection.
Dijin Xu1,2,3,4, Weiqian Jiang1,2,3, Lizhen Wu3
1Howard Hughes Medical Institute, New Haven, CT, USA.
Nature
|July 12, 2023
Summary
Phospholipid scramblase 1 (PLSCR1) acts as a cell-autonomous defense against SARS-CoV-2, including variants like Delta and Omicron. This protein blocks viral entry by targeting vesicles and preventing fusion, offering a new target for antiviral strategies.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Understanding protective immunity against SARS-CoV-2 is vital for pandemic preparedness and combating variants.
- While neutralizing antibodies are studied, local cell-autonomous defense mechanisms are also crucial.
- Previous research highlights the importance of host cell factors in controlling viral infections.
Purpose of the Study:
- To identify host cell factors involved in cell-autonomous defense against SARS-CoV-2.
- To investigate the role of phospholipid scramblase 1 (PLSCR1) in restricting SARS-CoV-2 infection.
- To elucidate the mechanism by which PLSCR1 inhibits viral entry.
Main Methods:
- Genome-wide CRISPR-Cas9 screens in human lung epithelia and hepatocytes.
- Interferon-gamma (IFNγ) stimulation to induce PLSCR1 expression.
- Infection assays with live SARS-CoV-2 (USA-WA1/2020, Delta, Omicron BA.1) and other coronaviruses.
- 4Pi single-molecule switching nanoscopy and bipartite nano-reporter assays.
- Functional conservation studies in bats and mice.
Main Results:
- PLSCR1 was identified as a potent cell-autonomous restriction factor against SARS-CoV-2.
- IFNγ-induced PLSCR1 restricted multiple SARS-CoV-2 lineages and other pathogenic coronaviruses.
- PLSCR1 interfered with both endocytic and TMPRSS2-dependent viral entry routes.
- PLSCR1 directly targeted viral vesicles, preventing spike-mediated fusion and viral escape.
- A C-terminal β-barrel domain of PLSCR1, not its lipid scramblase activity, was essential for blocking fusion.
Conclusions:
- PLSCR1 is a critical host defense protein that inhibits SARS-CoV-2 at a late stage of viral entry.
- PLSCR1's mechanism involves preventing fusion of viral vesicles with host cell membranes.
- PLSCR1 represents a potential therapeutic target for developing novel anti-coronavirus strategies.
- Understanding PLSCR1 function is important, especially considering COVID-associated mutations in susceptible individuals.
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