TY - JOUR
T1 - TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication
AU - Gonzalez-Orozco, Maria
AU - Tseng, Hsiang-chi
AU - Hage, Adam
AU - Xia, Hongjie
AU - Behera, Padmanava
AU - Afreen, Kazi
AU - Peñaflor-Tellez, Yoatzin
AU - Giraldo, Maria I.
AU - Huante, Matthew
AU - Puebla-Clark, Lucinda
AU - van Tol, Sarah
AU - Odle, Abby
AU - Crown, Matthew
AU - Teruel, Natalia
AU - Shelite, Thomas R.
AU - Moreno-Contreras, Joaquin
AU - Terasaki, Kaori
AU - Makino, Shinji
AU - Menachery, Vineet
AU - Endsley, Mark
AU - Endsley, Janice J.
AU - Najmanovich, Rafael J.
AU - Bashton, Matthew
AU - Stephens, Robin
AU - Shi, Pei-Yong
AU - Xie, Xuping
AU - Freiberg, Alexander N.
AU - Rajsbaum, Ricardo
PY - 2024/11/30
Y1 - 2024/11/30
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - COVID-19/virology
KW - Coronavirus M Proteins/metabolism
KW - Female
KW - HEK293 Cells
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mutation
KW - SARS-CoV-2/physiology
KW - Tripartite Motif Proteins/metabolism
KW - Ubiquitin-Protein Ligases/metabolism
KW - Ubiquitination
KW - Virus Replication
UR - http://www.scopus.com/inward/record.url?scp=85211150705&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-54762-5
DO - 10.1038/s41467-024-54762-5
M3 - Article
C2 - 39616206
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 10438
ER -