PLSCR1 suppresses SARS-CoV-2 infection by downregulating cell surface ACE2

Area of Science:

• Innate immunity
• Virology
• Molecular biology

Background:

• Type I interferons induce interferon-stimulated genes (ISGs) to combat SARS-CoV-2.
• The precise antiviral mechanisms of most ISGs against SARS-CoV-2 remain incompletely understood.
• Identifying novel host restriction factors is crucial for understanding viral pathogenesis and developing therapeutics.

Purpose of the Study:

• To identify novel interferon-stimulated genes (ISGs) that restrict SARS-CoV-2 (COVID-19) infection.
• To elucidate the mechanism by which phospholipid scramblase 1 (PLSCR1) inhibits SARS-CoV-2 entry.
• To explore the therapeutic potential of targeting PLSCR1-mediated restriction.

Main Methods:

• Screening of 109 ISG-knockout cell lines to identify antiviral factors.
• Utilizing pseudotyped and authentic SARS-CoV-2 to assess viral entry.
• Quantifying ACE2 expression on the plasma membrane and overall cellular levels.

Main Results:

• Phospholipid scramblase 1 (PLSCR1) was identified as a key restriction factor against SARS-CoV-2.
• PLSCR1-deficient cells exhibited increased susceptibility to SARS-CoV-2 infection.
• Overexpression of PLSCR1 inhibited SARS-CoV-2 infection by downregulating plasma membrane ACE2 expression.

Conclusions:

• PLSCR1 acts as a critical host restriction factor, inhibiting SARS-CoV-2 entry.
• The mechanism involves specific downregulation of plasma membrane ACE2, the viral receptor.
• These findings provide insights into host-innate immunity against SARS-CoV-2 and suggest potential antiviral therapeutic strategies.