Nature Communications (Nov 2024)
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
Affiliations
- Maria Gonzalez-Orozco
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Hsiang-chi Tseng
- Center for Virus-Host-Innate-Immunity, RBHS Institute for Infectious and Inflammatory Diseases, and Department of Medicine, New Jersey Medical School, Rutgers University
- Adam Hage
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Hongjie Xia
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch
- Padmanava Behera
- Center for Virus-Host-Innate-Immunity, RBHS Institute for Infectious and Inflammatory Diseases, and Department of Medicine, New Jersey Medical School, Rutgers University
- Kazi Afreen
- Center for Virus-Host-Innate-Immunity, RBHS Institute for Infectious and Inflammatory Diseases, and Department of Medicine, New Jersey Medical School, Rutgers University
- Yoatzin Peñaflor-Tellez
- Center for Virus-Host-Innate-Immunity, RBHS Institute for Infectious and Inflammatory Diseases, and Department of Medicine, New Jersey Medical School, Rutgers University
- Maria I. Giraldo
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Matthew Huante
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Lucinda Puebla-Clark
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch
- Sarah van Tol
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Abby Odle
- Center for Virus-Host-Innate-Immunity, RBHS Institute for Infectious and Inflammatory Diseases, and Department of Medicine, New Jersey Medical School, Rutgers University
- Matthew Crown
- Hub for Biotechnology in the Built Environment, Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University
- Natalia Teruel
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal
- Thomas R. Shelite
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch
- Joaquin Moreno-Contreras
- Center for Virus-Host-Innate-Immunity, RBHS Institute for Infectious and Inflammatory Diseases, and Department of Medicine, New Jersey Medical School, Rutgers University
- Kaori Terasaki
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Shinji Makino
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Vineet Menachery
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Mark Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Janice J. Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch
- Rafael J. Najmanovich
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal
- Matthew Bashton
- Hub for Biotechnology in the Built Environment, Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University
- Robin Stephens
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch
- Pei-Yong Shi
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch
- Xuping Xie
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch
- Alexander N. Freiberg
- Department of Pathology, University of Texas Medical Branch
- Ricardo Rajsbaum
- Department of Microbiology and Immunology, University of Texas Medical Branch
- DOI
- https://doi.org/10.1038/s41467-024-54762-5
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
