tetano
Editor, Senior Moderator
Nat Commun
. 2024 Nov 30;15(1):10438.
doi: 10.1038/s41467-024-54762-5. TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication
Maria Gonzalez-Orozco[SUP] 1 [/SUP], Hsiang-Chi Tseng[SUP] 2 [/SUP], Adam Hage[SUP] 1 [/SUP], Hongjie Xia[SUP] 3 [/SUP], Padmanava Behera[SUP] 2 [/SUP], Kazi Afreen[SUP] 2 [/SUP], Yoatzin Peñaflor-Tellez[SUP] 2 [/SUP], Maria I Giraldo[SUP] 1 [/SUP], Matthew Huante[SUP] 1 [/SUP], Lucinda Puebla-Clark[SUP] 4 [/SUP], Sarah van Tol[SUP] 1 [/SUP], Abby Odle[SUP] 2 [/SUP], Matthew Crown[SUP] 5 [/SUP], Natalia Teruel[SUP] 6 [/SUP], Thomas R Shelite[SUP] 4 [/SUP], Joaquin Moreno-Contreras[SUP] 2 [/SUP], Kaori Terasaki[SUP] 1 [/SUP], Shinji Makino[SUP] 1 [/SUP], Vineet Menachery[SUP] 1 [/SUP], Mark Endsley[SUP] 1 [/SUP], Janice J Endsley[SUP] 1 [/SUP], Rafael J Najmanovich[SUP] 6 [/SUP], Matthew Bashton[SUP] 5 [/SUP], Robin Stephens[SUP] 4 7 [/SUP], Pei-Yong Shi[SUP] 3 [/SUP], Xuping Xie[SUP] 3 [/SUP], Alexander N Freiberg[SUP] 8 [/SUP], Ricardo Rajsbaum[SUP] 9 10 [/SUP]
Affiliations
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[SUP]-/-[/SUP] 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.
. 2024 Nov 30;15(1):10438.
doi: 10.1038/s41467-024-54762-5. TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication
Maria Gonzalez-Orozco[SUP] 1 [/SUP], Hsiang-Chi Tseng[SUP] 2 [/SUP], Adam Hage[SUP] 1 [/SUP], Hongjie Xia[SUP] 3 [/SUP], Padmanava Behera[SUP] 2 [/SUP], Kazi Afreen[SUP] 2 [/SUP], Yoatzin Peñaflor-Tellez[SUP] 2 [/SUP], Maria I Giraldo[SUP] 1 [/SUP], Matthew Huante[SUP] 1 [/SUP], Lucinda Puebla-Clark[SUP] 4 [/SUP], Sarah van Tol[SUP] 1 [/SUP], Abby Odle[SUP] 2 [/SUP], Matthew Crown[SUP] 5 [/SUP], Natalia Teruel[SUP] 6 [/SUP], Thomas R Shelite[SUP] 4 [/SUP], Joaquin Moreno-Contreras[SUP] 2 [/SUP], Kaori Terasaki[SUP] 1 [/SUP], Shinji Makino[SUP] 1 [/SUP], Vineet Menachery[SUP] 1 [/SUP], Mark Endsley[SUP] 1 [/SUP], Janice J Endsley[SUP] 1 [/SUP], Rafael J Najmanovich[SUP] 6 [/SUP], Matthew Bashton[SUP] 5 [/SUP], Robin Stephens[SUP] 4 7 [/SUP], Pei-Yong Shi[SUP] 3 [/SUP], Xuping Xie[SUP] 3 [/SUP], Alexander N Freiberg[SUP] 8 [/SUP], Ricardo Rajsbaum[SUP] 9 10 [/SUP]
Affiliations
- PMID: 39616206
- PMCID: PMC11608229
- DOI: 10.1038/s41467-024-54762-5
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[SUP]-/-[/SUP] 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.