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.

Details

Title
Inhibition of HECT E3 ligases as potential therapy for COVID-19
Author
Novelli Giuseppe 1   VIAFID ORCID Logo  ; Liu, Jing 2 ; Biancolella Michela 3 ; Alonzi Tonino 4 ; Novelli, Antonio 5 ; Patten, J J 6   VIAFID ORCID Logo  ; Cocciadiferro Dario 5 ; Agolini Emanuele 5   VIAFID ORCID Logo  ; Colona Vito Luigi 7   VIAFID ORCID Logo  ; Rizzacasa, Barbara 7   VIAFID ORCID Logo  ; Giannini Rosalinda 7 ; Bigio Benedetta 8 ; Goletti Delia 4 ; Capobianchi Maria Rosaria 9 ; Grelli Sandro 10 ; Mann, Justin 11 ; McKee, Trevor D 11 ; Cheng, Ke 11 ; Amanat Fatima 12 ; Krammer Florian 12 ; Guarracino, Andrea 3   VIAFID ORCID Logo  ; Pepe, Gerardo 3   VIAFID ORCID Logo  ; Tomino Carlo 13 ; Tandjaoui-Lambiotte Yacine 14 ; Uzunhan Yurdagul 15 ; Tubiana Sarah 16 ; Ghosn Jade 17 ; Notarangelo, Luigi D 18 ; Su, Helen C 18 ; Abel, Laurent 19 ; Cobat Aurélie 19 ; Gai, Elhanan 20 ; Grzymski, Joseph J 20 ; Latini, Andrea 7 ; Sidhu, Sachdev S 21 ; Jain Suresh 22 ; Davey, Robert A 23 ; Jean-Laurent, Casanova 24 ; Wei, Wenyi 2 ; Pandolfi, Pier Paolo 25 

1  Tor Vergata University of Rome, Department of Biomedicine and Prevention, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941); IRCCS Neuromed, Pozzilli, Italy (GRID:grid.419543.e) (ISNI:0000 0004 1760 3561); University of Nevada, Department of Pharmacology, School of Medicine, Reno, USA (GRID:grid.266818.3) (ISNI:0000 0004 1936 914X) 
2  Harvard Medical School, Department of Pathology, Beth Israel Deaconess Cancer Center, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
3  Tor Vergata University, Department of Biology, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941) 
4  National Institute for Infectious Diseases Lazzaro Spallanzani – IRCCS, Translational Research Unit, Department of Epidemiology and Preclinical Research, Rome, Italy (GRID:grid.419423.9) (ISNI:0000 0004 1760 4142) 
5  IRCCS Bambino Gesù Children’s Hospital, Laboratory of Medical Genetics, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809) 
6  Boston University, National Emerging Infectious Diseases Laboratories, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
7  Tor Vergata University of Rome, Department of Biomedicine and Prevention, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941) 
8  Rockefeller Branch, Rockefeller University, St. Giles Laboratory of Human Genetics of Infectious Diseases, New York, USA (GRID:grid.134907.8) (ISNI:0000 0001 2166 1519) 
9  National Institute for Infectious Diseases Lazzaro Spallanzani – IRCCS, Laboratory of Virology, Department of Epidemiology and Preclinical Research, Rome, Italy (GRID:grid.419423.9) (ISNI:0000 0004 1760 4142) 
10  Tor Vergata University of Rome, Department of Experimental Medicine, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941) 
11  HistoWiz Inc, Brooklyn, USA (GRID:grid.6530.0) 
12  Icahn school of Medicine at Mount Sinai, Department of Microbiology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
13  San Raffaele University of Rome, Rome, Italy (GRID:grid.466134.2) (ISNI:0000 0004 4912 5648) 
14  Avicenne Hospital, APHP, Intensive Care Unit, Bobigny, France (GRID:grid.413780.9) (ISNI:0000 0000 8715 2621); INSERM U1272 Hypoxia & Lung, Bobigny, France (GRID:grid.413780.9) 
15  Hôpital Avicenne, APHP, Bobigny; INSERM UMR1272, Université Paris 13, Pneumology Department, Reference Center for Rare Pulmonary Diseases, Bobigny, France (GRID:grid.413780.9) (ISNI:0000 0000 8715 2621) 
16  Hôpital Bichat Claude Bernard, APHP, Paris, France (GRID:grid.411119.d) (ISNI:0000 0000 8588 831X); Centre d’investigation Clinique, Inserm CIC, Paris, France (GRID:grid.411119.d) 
17  INSERM, UMRS1137, University of Paris, Infection, Antimicrobials, Modelling, Evolution (IAME), Paris, France (GRID:grid.411119.d); AP-HP, Bichat Claude Bernard Hospital, Infectious and Tropical Disease Department, Paris, France (GRID:grid.411119.d) 
18  Laboratory of Clinical Immunology, NIAID, NIH, Bethesda, USA (GRID:grid.411119.d) 
19  Rockefeller Branch, Rockefeller University, St. Giles Laboratory of Human Genetics of Infectious Diseases, New York, USA (GRID:grid.134907.8) (ISNI:0000 0001 2166 1519); Necker Hospital for Sick Children, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France (GRID:grid.412134.1) (ISNI:0000 0004 0593 9113); University of Paris, Imagine Institute, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
20  Center for Genomic Medicine, Desert Research Institute, Reno, USA (GRID:grid.474431.1) (ISNI:0000 0004 0525 4843); Renown Institute for Cancer, Nevada System of Higher Education, Reno, USA (GRID:grid.298261.6) (ISNI:0000 0000 8685 5368) 
21  University of Toronto, The Donnelly Centre, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
22  Virna Therapeutics, West Roxbury, USA (GRID:grid.17063.33) 
23  National Emerging Infectious Diseases Laboratories, Department of Microbiology Boston University, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
24  Rockefeller Branch, Rockefeller University, St. Giles Laboratory of Human Genetics of Infectious Diseases, New York, USA (GRID:grid.134907.8) (ISNI:0000 0001 2166 1519); Necker Hospital for Sick Children, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France (GRID:grid.412134.1) (ISNI:0000 0004 0593 9113); University of Paris, Imagine Institute, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602); Howard Hughes Medical Institute, New York, USA (GRID:grid.413575.1) (ISNI:0000 0001 2167 1581) 
25  Harvard Medical School, Department of Pathology, Beth Israel Deaconess Cancer Center, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Renown Institute for Cancer, Nevada System of Higher Education, Reno, USA (GRID:grid.298261.6) (ISNI:0000 0000 8685 5368); University of Turin, MBC, Department of Molecular Biotechnology and Health Sciences, Turin, Italy (GRID:grid.7605.4) (ISNI:0000 0001 2336 6580) 
Publication year
2021
Publication date
Mar 2021
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-021-03513-1
ProQuest document ID
2504628360
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.