tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2021 Oct 19;118(42):e2113401118.
doi: 10.1073/pnas.2113401118. Epub 2021 Sep 30.
Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition
Xiaolei Liu[SUP] 1 [/SUP], Anurag Verma[SUP] 1 2 [/SUP], Gustavo Garcia Jr[SUP] 3 [/SUP], Holly Ramage[SUP] 4 [/SUP], Anastasia Lucas[SUP] 2 [/SUP], Rebecca L Myers[SUP] 5 [/SUP], Jacob J Michaelson[SUP] 6 [/SUP], William Coryell[SUP] 6 [/SUP], Arvind Kumar[SUP] 7 [/SUP], Alexander W Charney[SUP] 8 9 10 7 [/SUP], Marcelo G Kazanietz[SUP] 11 [/SUP], Daniel J Rader[SUP] 1 2 [/SUP], Marylyn D Ritchie[SUP] 2 [/SUP], Wade H Berrettini[SUP] 12 [/SUP], David C Schultz[SUP] 13 [/SUP], Sara Cherry[SUP] 4 13 14 [/SUP], Robert Damoiseaux[SUP] 3 15 16 17 18 [/SUP], Vaithilingaraja Arumugaswami[SUP] 3 [/SUP], Peter S Klein[SUP] 19 [/SUP]
Affiliations
Abstract
The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-CoV, and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors, including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR-tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35-0.74], P = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type-dependent manner. Targeting GSK-3 may therefore provide an approach to treat COVID-19 and future coronavirus outbreaks.
Keywords: COVID19; GSK-3; coronavirus; lithium; nucleocapsid.
. 2021 Oct 19;118(42):e2113401118.
doi: 10.1073/pnas.2113401118. Epub 2021 Sep 30.
Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition
Xiaolei Liu[SUP] 1 [/SUP], Anurag Verma[SUP] 1 2 [/SUP], Gustavo Garcia Jr[SUP] 3 [/SUP], Holly Ramage[SUP] 4 [/SUP], Anastasia Lucas[SUP] 2 [/SUP], Rebecca L Myers[SUP] 5 [/SUP], Jacob J Michaelson[SUP] 6 [/SUP], William Coryell[SUP] 6 [/SUP], Arvind Kumar[SUP] 7 [/SUP], Alexander W Charney[SUP] 8 9 10 7 [/SUP], Marcelo G Kazanietz[SUP] 11 [/SUP], Daniel J Rader[SUP] 1 2 [/SUP], Marylyn D Ritchie[SUP] 2 [/SUP], Wade H Berrettini[SUP] 12 [/SUP], David C Schultz[SUP] 13 [/SUP], Sara Cherry[SUP] 4 13 14 [/SUP], Robert Damoiseaux[SUP] 3 15 16 17 18 [/SUP], Vaithilingaraja Arumugaswami[SUP] 3 [/SUP], Peter S Klein[SUP] 19 [/SUP]
Affiliations
- PMID: 34593624
- DOI: 10.1073/pnas.2113401118
Abstract
The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-CoV, and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors, including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR-tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35-0.74], P = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type-dependent manner. Targeting GSK-3 may therefore provide an approach to treat COVID-19 and future coronavirus outbreaks.
Keywords: COVID19; GSK-3; coronavirus; lithium; nucleocapsid.