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; 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; Ricardo Rajsbaum

doi:10.1038/s41467-024-54762-5

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, Joaquin Moreno-Contreras, Kaori Terasaki, Shinji Makino, Vineet Menachery, Mark EndsleyJanice J. Endsley, Rafael J. Najmanovich, Matthew Bashton, Robin Stephens, Pei-Yong Shi, Xuping Xie, Alexander N. Freiberg, Ricardo Rajsbaum^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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. 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.

Original language	English
Article number	10438
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-54762-5
Publication status	Published - 30 Nov 2024

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Animals
Apoptosis
COVID-19/virology
Coronavirus M Proteins/metabolism
Female
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
SARS-CoV-2/physiology
Tripartite Motif Proteins/metabolism
Ubiquitin-Protein Ligases/metabolism
Ubiquitination
Virus Replication

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s41467-024-54762-5Final published version, 2.13 MBLicence: CC BY-NC-ND

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Gonzalez-Orozco, M., Tseng, H., 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., ... Rajsbaum, R. (2024). TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication. Nature Communications, 15(1), Article 10438. https://doi.org/10.1038/s41467-024-54762-5

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title = "TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication",

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.",

keywords = "Animals, Apoptosis, COVID-19/virology, Coronavirus M Proteins/metabolism, Female, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, SARS-CoV-2/physiology, Tripartite Motif Proteins/metabolism, Ubiquitin-Protein Ligases/metabolism, Ubiquitination, Virus Replication",

author = "Maria Gonzalez-Orozco and Hsiang-chi Tseng and Adam Hage and Hongjie Xia and Padmanava Behera and Kazi Afreen and Yoatzin Pe{\~n}aflor-Tellez and Giraldo, \{Maria I.\} and Matthew Huante and Lucinda Puebla-Clark and \{van Tol\}, Sarah and Abby Odle and Matthew Crown and Natalia Teruel and Shelite, \{Thomas R.\} and Joaquin Moreno-Contreras and Kaori Terasaki and Shinji Makino and Vineet Menachery and Mark Endsley and Endsley, \{Janice J.\} and Najmanovich, \{Rafael J.\} and Matthew Bashton and Robin Stephens and Pei-Yong Shi and Xuping Xie and Freiberg, \{Alexander N.\} and Ricardo Rajsbaum",

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month = nov,

day = "30",

doi = "10.1038/s41467-024-54762-5",

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Gonzalez-Orozco, M, Tseng, H, 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, Moreno-Contreras, J, Terasaki, K, Makino, S, 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', Nature Communications, vol. 15, no. 1, 10438. https://doi.org/10.1038/s41467-024-54762-5

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 - https://www.scopus.com/pages/publications/85211150705

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 -

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

Abstract

UN SDGs

Keywords

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

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