Cell Death and Disease (Mar 2021)
Inhibition of HECT E3 ligases as potential therapy for COVID-19
- Giuseppe Novelli,
- Jing Liu,
- Michela Biancolella,
- Tonino Alonzi,
- Antonio Novelli,
- J. J. Patten,
- Dario Cocciadiferro,
- Emanuele Agolini,
- Vito Luigi Colona,
- Barbara Rizzacasa,
- Rosalinda Giannini,
- Benedetta Bigio,
- Delia Goletti,
- Maria Rosaria Capobianchi,
- Sandro Grelli,
- Justin Mann,
- Trevor D. McKee,
- Ke Cheng,
- Fatima Amanat,
- Florian Krammer,
- Andrea Guarracino,
- Gerardo Pepe,
- Carlo Tomino,
- Yacine Tandjaoui-Lambiotte,
- Yurdagul Uzunhan,
- Sarah Tubiana,
- Jade Ghosn,
- COVID Human Genetic Effort,
- French COVID Cohort Study Group,
- CoV-Contact Cohort,
- Luigi D. Notarangelo,
- Helen C. Su,
- Laurent Abel,
- Aurélie Cobat,
- Gai Elhanan,
- Joseph J. Grzymski,
- Andrea Latini,
- Sachdev S. Sidhu,
- Suresh Jain,
- Robert A. Davey,
- Jean-Laurent Casanova,
- Wenyi Wei,
- Pier Paolo Pandolfi
Affiliations
- Giuseppe Novelli
- Department of Biomedicine and Prevention, Tor Vergata University of Rome
- Jing Liu
- Department of Pathology, Beth Israel Deaconess Cancer Center, Harvard Medical School
- Michela Biancolella
- Department of Biology, Tor Vergata University
- Tonino Alonzi
- Translational Research Unit, Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases Lazzaro Spallanzani – IRCCS
- Antonio Novelli
- Laboratory of Medical Genetics, IRCCS Bambino Gesù Children’s Hospital
- J. J. Patten
- National Emerging Infectious Diseases Laboratories, Boston University
- Dario Cocciadiferro
- Laboratory of Medical Genetics, IRCCS Bambino Gesù Children’s Hospital
- Emanuele Agolini
- Laboratory of Medical Genetics, IRCCS Bambino Gesù Children’s Hospital
- Vito Luigi Colona
- Department of Biomedicine and Prevention, Tor Vergata University of Rome
- Barbara Rizzacasa
- Department of Biomedicine and Prevention, Tor Vergata University of Rome
- Rosalinda Giannini
- Department of Biomedicine and Prevention, Tor Vergata University of Rome
- Benedetta Bigio
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University
- Delia Goletti
- Translational Research Unit, Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases Lazzaro Spallanzani – IRCCS
- Maria Rosaria Capobianchi
- Laboratory of Virology, Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases Lazzaro Spallanzani – IRCCS
- Sandro Grelli
- Department of Experimental Medicine, Tor Vergata University of Rome
- Justin Mann
- HistoWiz Inc
- Trevor D. McKee
- HistoWiz Inc
- Ke Cheng
- HistoWiz Inc
- Fatima Amanat
- Department of Microbiology, Icahn school of Medicine at Mount Sinai
- Florian Krammer
- Department of Microbiology, Icahn school of Medicine at Mount Sinai
- Andrea Guarracino
- Department of Biology, Tor Vergata University
- Gerardo Pepe
- Department of Biology, Tor Vergata University
- Carlo Tomino
- San Raffaele University of Rome
- Yacine Tandjaoui-Lambiotte
- Intensive Care Unit, Avicenne Hospital, APHP
- Yurdagul Uzunhan
- Pneumology Department, Reference Center for Rare Pulmonary Diseases, Hôpital Avicenne, APHP, Bobigny; INSERM UMR1272, Université Paris 13
- Sarah Tubiana
- Hôpital Bichat Claude Bernard, APHP
- Jade Ghosn
- Infection, Antimicrobials, Modelling, Evolution (IAME), INSERM, UMRS1137, University of Paris
- COVID Human Genetic Effort
- French COVID Cohort Study Group
- CoV-Contact Cohort
- Luigi D. Notarangelo
- Laboratory of Clinical Immunology, NIAID, NIH
- Helen C. Su
- Laboratory of Clinical Immunology, NIAID, NIH
- Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University
- Aurélie Cobat
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University
- Gai Elhanan
- Center for Genomic Medicine, Desert Research Institute
- Joseph J. Grzymski
- Center for Genomic Medicine, Desert Research Institute
- Andrea Latini
- Department of Biomedicine and Prevention, Tor Vergata University of Rome
- Sachdev S. Sidhu
- The Donnelly Centre, University of Toronto
- Suresh Jain
- Virna Therapeutics
- Robert A. Davey
- Department of Microbiology Boston University, National Emerging Infectious Diseases Laboratories
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University
- Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Cancer Center, Harvard Medical School
- Pier Paolo Pandolfi
- Department of Pathology, Beth Israel Deaconess Cancer Center, Harvard Medical School
- DOI
- https://doi.org/10.1038/s41419-021-03513-1
- Journal volume & issue
-
Vol. 12,
no. 4
pp. 1 – 18
Abstract
Abstract 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.
