TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication

Maria Gonzalez-Orozco, Hsiang-chi Tseng, Adam Hage, Hongjie Xia, Padmanava Behera, Kazi Afreen, Yoatzin Peñaflor-Tellez, Maria I. Giraldo, Matthew Huante, Lucinda Puebla-Clark, Sarah Tol, Abby Odle, Matthew Crown, Natalia Teruel, Thomas R. Shelite, Joaquin Moreno-Contreras, Kaori Terasaki, Shinji Makino, Vineet Menachery, Mark Endsley, Janice J. Endsley, Rafael J. Najmanovich, Matthew Bashton, Robin Stephens, Pei-Yong Shi, Xuping Xie, Alexander N. Freiberg and Ricardo Rajsbaum ()
Additional contact information
Maria Gonzalez-Orozco: University of Texas Medical Branch
Hsiang-chi Tseng: Rutgers University
Adam Hage: University of Texas Medical Branch
Hongjie Xia: University of Texas Medical Branch
Padmanava Behera: Rutgers University
Kazi Afreen: Rutgers University
Yoatzin Peñaflor-Tellez: Rutgers University
Maria I. Giraldo: University of Texas Medical Branch
Matthew Huante: University of Texas Medical Branch
Lucinda Puebla-Clark: University of Texas Medical Branch
Sarah Tol: University of Texas Medical Branch
Abby Odle: Rutgers University
Matthew Crown: Northumbria University
Natalia Teruel: Université de Montréal
Thomas R. Shelite: University of Texas Medical Branch
Joaquin Moreno-Contreras: Rutgers University
Kaori Terasaki: University of Texas Medical Branch
Shinji Makino: University of Texas Medical Branch
Vineet Menachery: University of Texas Medical Branch
Mark Endsley: University of Texas Medical Branch
Janice J. Endsley: University of Texas Medical Branch
Rafael J. Najmanovich: Université de Montréal
Matthew Bashton: Northumbria University
Robin Stephens: University of Texas Medical Branch
Pei-Yong Shi: University of Texas Medical Branch
Xuping Xie: University of Texas Medical Branch
Alexander N. Freiberg: University of Texas Medical Branch
Ricardo Rajsbaum: University of Texas Medical Branch

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. Here we show that the host E3-ubiquitin ligase TRIM7 acts as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7-/- mice exhibit increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients reveal that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M-K14/K15R virus shows reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.

Date: 2024
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DOI: 10.1038/s41467-024-54762-5

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