TY - JOUR
T1 - Inhibition of HECT E3 ligases as potential therapy for COVID-19
AU - COVID Human Genetic Effort
AU - French COVID Cohort Study Group
AU - CoV-Contact Cohort
AU - Novelli, Giuseppe
AU - Liu, Jing
AU - Biancolella, Michela
AU - Alonzi, Tonino
AU - Novelli, Antonio
AU - Patten, J. J.
AU - Cocciadiferro, Dario
AU - Agolini, Emanuele
AU - Colona, Vito Luigi
AU - Rizzacasa, Barbara
AU - Giannini, Rosalinda
AU - Bigio, Benedetta
AU - Goletti, Delia
AU - Capobianchi, Maria Rosaria
AU - Grelli, Sandro
AU - Mann, Justin
AU - McKee, Trevor D.
AU - Cheng, Ke
AU - Amanat, Fatima
AU - Krammer, Florian
AU - Guarracino, Andrea
AU - Pepe, Gerardo
AU - Tomino, Carlo
AU - Tandjaoui-Lambiotte, Yacine
AU - Uzunhan, Yurdagul
AU - Tubiana, Sarah
AU - Ghosn, Jade
AU - Notarangelo, Luigi D.
AU - Su, Helen C.
AU - Abel, Laurent
AU - Cobat, Aurélie
AU - Elhanan, Gai
AU - Grzymski, Joseph J.
AU - Latini, Andrea
AU - Sidhu, Sachdev S.
AU - Jain, Suresh
AU - Davey, Robert A.
AU - Casanova, Jean Laurent
AU - Wei, Wenyi
AU - Pandolfi, Pier Paolo
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85103504743
U2 - 10.1038/s41419-021-03513-1
DO - 10.1038/s41419-021-03513-1
M3 - 文章
C2 - 33762578
AN - SCOPUS:85103504743
SN - 2041-4889
VL - 12
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 4
M1 - 310
ER -
SDG 3 Good Health and Well-being