TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2.

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2) to infect human cells.
• ACE2 expression levels influence COVID-19 susceptibility and severity.
• The role of Tripartite motif containing 28 (TRIM28) in ACE2 regulation and SARS-CoV-2 entry was previously unclear.

Purpose of the Study:

• To investigate the role of TRIM28 in regulating ACE2 expression.
• To determine the effect of TRIM28 on SARS-CoV-2 cell entry.
• To elucidate the interaction between NK cells, TRIM28, and ACE2 expression.

Main Methods:

• TRIM28 knockdown in A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs).
• Pseudotyped SARS-CoV-2 entry assays.
• Co-culture models of NK cells and lung epithelial cells.
• Interferon-gamma (IFN-γ) stimulation and receptor analysis.
• Dexamethasone treatment.

Main Results:

• TRIM28 knockdown significantly increased ACE2 expression and SARS-CoV-2 pseudotyped virus entry.
• NK cells inhibited TRIM28 and promoted ACE2 expression in lung epithelial cells, partly via interleukin-2 and granzyme B.
• TRIM28 knockdown enhanced IFN-γ-induced ACE2 expression by upregulating IFN-γ receptor 2 (IFNGR2).
• Dexamethasone partially reversed ACE2 upregulation induced by TRIM28 knockdown and NK cell co-culture.

Conclusions:

• TRIM28 is identified as a novel negative regulator of ACE2 expression.
• TRIM28 influences SARS-CoV-2 cell entry.
• NK cell activity and IFN-γ signaling pathways modulate ACE2 expression through TRIM28.
• Targeting TRIM28 may offer a strategy to control SARS-CoV-2 infection.