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 van Tol; Abby Odle; Matthew Crown; Natalia Teruel; Thomas R. Shelite; Vineet Menachery; Mark Endsley; Janice J. Endsley; Rafael J. Najmanovich; Matthew Bashton; Robin Stephens; Pei-Yong Shi; Xuping Xie; Alexander N. Freiberg; Ricardo Rajsbaum

doi:10.1101/2024.06.17.599107

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 van Tol, Abby Odle, Matthew Crown, Natalia Teruel, Thomas R. Shelite, Vineet Menachery, Mark Endsley, Janice J. Endsley, Rafael J. Najmanovich, Matthew BashtonRobin Stephens, Pei-Yong Shi, Xuping Xie, Alexander N. Freiberg, Ricardo Rajsbaum

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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. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibited 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 revealed 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 showed 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.

Original language	English
Place of Publication	Cold Harbor, US
Publisher	Cold Spring Harbor Laboratory Press
Pages	1-36
Number of pages	36
DOIs	https://doi.org/10.1101/2024.06.17.599107
Publication status	Submitted - 17 Jun 2024

Keywords

SARS-CoV-2
Membrane protein
E3-Ubiquitin ligases
TRIM7
Ubiquitination
Apoptosis
Antiviral activity
Caspase-6

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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2024.06.17.599107v1.fullSubmitted manuscript, 1.61 MBLicence: CC BY-NC-ND

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TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication
Gonzalez-Orozco, M., Tseng, H.-C., Hage, A., Xia, H., Behera, P., Afreen, K., Peñaflor-Tellez, Y., Giraldo, M. I., Huante, M., Puebla-Clark, L., van Tol, S., Odle, A., Crown, M., Teruel, N., Shelite, T. R., Moreno-Contreras, J., Terasaki, K., Makino, S., Menachery, V. & Endsley, M. & 8 others, Endsley, J. J., Najmanovich, R. J., Bashton, M., Stephens, R., Shi, P.-Y., Xie, X., Freiberg, A. N. & Rajsbaum, R., 30 Nov 2024, In: Nature Communications. 15, 1, 10438.
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Gonzalez-Orozco, M., Tseng, H.-C., Hage, A., Xia, H., Behera, P., Afreen, K., Peñaflor-Tellez, Y., Giraldo, M. I., Huante, M., Puebla-Clark, L., van Tol, S., Odle, A., Crown, M., Teruel, N., Shelite, T. R., Menachery, V., Endsley, M., Endsley, J. J., Najmanovich, R. J., ... Rajsbaum, R. (2024). TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication. (pp. 1-36). Cold Spring Harbor Laboratory Press. https://doi.org/10.1101/2024.06.17.599107

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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. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibited 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 revealed 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 showed 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. ",

keywords = "SARS-CoV-2, Membrane protein, E3-Ubiquitin ligases, TRIM7, Ubiquitination, Apoptosis, Antiviral activity, Caspase-6",

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doi = "10.1101/2024.06.17.599107",

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Gonzalez-Orozco, M, Tseng, H-C, Hage, A, Xia, H, Behera, P, Afreen, K, Peñaflor-Tellez, Y, Giraldo, MI, Huante, M, Puebla-Clark, L, van Tol, S, Odle, A, Crown, M, Teruel, N, Shelite, TR, Menachery, V, Endsley, M, Endsley, JJ, Najmanovich, RJ, Bashton, M, Stephens, R, Shi, P-Y, Xie, X, Freiberg, AN & Rajsbaum, R 2024 'TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication' Cold Spring Harbor Laboratory Press, Cold Harbor, US, pp. 1-36. https://doi.org/10.1101/2024.06.17.599107

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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 - Menachery, Vineet

AU - Endsley, Mark

AU - Endsley, Janice J.

AU - Najmanovich, Rafael J.

AU - Bashton, Matthew

AU - Stephens, Robin

AU - Shi, Pei-Yong

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AU - Freiberg, Alexander N.

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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. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibited 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 revealed 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 showed 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.

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