期刊
CELL DEATH & DISEASE
卷 12, 期 4, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-021-03513-1
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资金
- Howard Hughes Medical Institute
- Rockefeller University
- St. Giles Foundation
- NIH [R01AI088364]
- National Center for Advancing Translational Sciences (NCATS)
- NIH Clinical and Translational Science Award (CTSA) program [UL1 TR001866]
- Emergent Ventures, Mercatus Center at George Mason University
- Yale Center for Mendelian Genomics
- GSP Coordinating Center - National Human Genome Research Institute (NHGRI) [UM1HG006504, U24HG008956]
- French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01]
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- French Foundation for Medical Research (FRM) [EQU201903007798]
- FRM and ANR GENCOVID project [ANRS-COV05]
- Square Foundation
- Grandir-Fonds de Solidarite pour l'Enfance
- SCOR Corporate Foundation for Science
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- University of Paris
- Inserm
- REACTing consortium
- French Ministry of Health [PHRC 20-0424]
- Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health
- Rome Foundation (Italy) [317 A/I]
HECT family E3 ligases are identified as potential biomarkers for COVID-19, with rare germline activating variants in NEDD4 and WWP1 genes associated with severe cases. Natural inhibitors I3C from Brassicaceae show potent antiviral effects against SARS-CoV-2, making them potential targets for therapeutic strategies easily testable in clinical trials.
SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.
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