tetano
Editor, Senior Moderator
Cell
. 2020 Jun 28;S0092-8674(20)30811-4.
doi: 10.1016/j.cell.2020.06.034. Online ahead of print.
The Global Phosphorylation Landscape of SARS-CoV-2 Infection
Mehdi Bouhaddou[SUP] 1 [/SUP], Danish Memon[SUP] 2 [/SUP], Bjoern Meyer[SUP] 3 [/SUP], Kris M White[SUP] 4 [/SUP], Veronica V Rezelj[SUP] 3 [/SUP], Miguel Correa Marrero[SUP] 2 [/SUP], Benjamin J Polacco[SUP] 1 [/SUP], James E Melnyk[SUP] 5 [/SUP], Svenja Ulferts[SUP] 6 [/SUP], Robyn M Kaake[SUP] 1 [/SUP], Jyoti Batra[SUP] 1 [/SUP], Alicia L Richards[SUP] 1 [/SUP], Erica Stevenson[SUP] 1 [/SUP], David E Gordon[SUP] 1 [/SUP], Ajda Rojc[SUP] 1 [/SUP], Kirsten Obernier[SUP] 1 [/SUP], Jacqueline M Fabius[SUP] 1 [/SUP], Margaret Soucheray[SUP] 1 [/SUP], Lisa Miorin[SUP] 4 [/SUP], Elena Moreno[SUP] 4 [/SUP], Cassandra Koh[SUP] 3 [/SUP], Quang Dinh Tran[SUP] 3 [/SUP], Alexandra Hardy[SUP] 3 [/SUP], R?my Robinot[SUP] 7 [/SUP], Thomas Vallet[SUP] 3 [/SUP], Benjamin E Nilsson-Payant[SUP] 8 [/SUP], Claudia Hernandez-Armenta[SUP] 2 [/SUP], Alistair Dunham[SUP] 2 [/SUP], Sebastian Weigang[SUP] 9 [/SUP], Julian Knerr[SUP] 6 [/SUP], Maya Modak[SUP] 1 [/SUP], Diego Quintero[SUP] 1 [/SUP], Yuan Zhou[SUP] 1 [/SUP], Aurelien Dugourd[SUP] 10 [/SUP], Alberto Valdeolivas[SUP] 10 [/SUP], Trupti Patil[SUP] 1 [/SUP], Qiongyu Li[SUP] 1 [/SUP], Ruth H?ttenhain[SUP] 1 [/SUP], Merve Cakir[SUP] 1 [/SUP], Monita Muralidharan[SUP] 1 [/SUP], Minkyu Kim[SUP] 1 [/SUP], Gwendolyn Jang[SUP] 1 [/SUP], Beril Tutuncuoglu[SUP] 1 [/SUP], Joseph Hiatt[SUP] 1 [/SUP], Jeffrey Z Guo[SUP] 1 [/SUP], Jiewei Xu[SUP] 1 [/SUP], Sophia Bouhaddou[SUP] 11 [/SUP], Christopher J P Mathy[SUP] 12 [/SUP], Anna Gaulton[SUP] 2 [/SUP], Emma J Manners[SUP] 2 [/SUP], Eloy F?lix[SUP] 2 [/SUP], Ying Shi[SUP] 5 [/SUP], Marisa Goff[SUP] 8 [/SUP], Jean K Lim[SUP] 8 [/SUP], Timothy McBride[SUP] 13 [/SUP], Michael C O'Neal[SUP] 13 [/SUP], Yiming Cai[SUP] 13 [/SUP], Jason C J Chang[SUP] 13 [/SUP], David J Broadhurst[SUP] 13 [/SUP], Saker Klippsten[SUP] 13 [/SUP], Emmie De Wit[SUP] 14 [/SUP], Andrew R Leach[SUP] 2 [/SUP], Tanja Kortemme[SUP] 12 [/SUP], Brian Shoichet[SUP] 15 [/SUP], Melanie Ott[SUP] 16 [/SUP], Julio Saez-Rodriguez[SUP] 9 [/SUP], Benjamin R tenOever[SUP] 8 [/SUP], R Dyche Mullins[SUP] 17 [/SUP], Elizabeth R Fischer[SUP] 14 [/SUP], Georg Kochs[SUP] 18 [/SUP], Robert Grosse[SUP] 19 [/SUP], Adolfo Garc?a-Sastre[SUP] 20 [/SUP], Marco Vignuzzi[SUP] 21 [/SUP], Jeffery R Johnson[SUP] 22 [/SUP], Kevan M Shokat[SUP] 23 [/SUP], Danielle L Swaney[SUP] 24 [/SUP], Pedro Beltrao[SUP] 25 [/SUP], Nevan J Krogan[SUP] 26 [/SUP]
Affiliations
Abstract
The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.
Keywords: AXL; CDK; MAPK; PIKFYVE; SARS-CoV-2; antiviral; casein kinase II; mass spectrometry; p38; phosphoproteomics.
. 2020 Jun 28;S0092-8674(20)30811-4.
doi: 10.1016/j.cell.2020.06.034. Online ahead of print.
The Global Phosphorylation Landscape of SARS-CoV-2 Infection
Mehdi Bouhaddou[SUP] 1 [/SUP], Danish Memon[SUP] 2 [/SUP], Bjoern Meyer[SUP] 3 [/SUP], Kris M White[SUP] 4 [/SUP], Veronica V Rezelj[SUP] 3 [/SUP], Miguel Correa Marrero[SUP] 2 [/SUP], Benjamin J Polacco[SUP] 1 [/SUP], James E Melnyk[SUP] 5 [/SUP], Svenja Ulferts[SUP] 6 [/SUP], Robyn M Kaake[SUP] 1 [/SUP], Jyoti Batra[SUP] 1 [/SUP], Alicia L Richards[SUP] 1 [/SUP], Erica Stevenson[SUP] 1 [/SUP], David E Gordon[SUP] 1 [/SUP], Ajda Rojc[SUP] 1 [/SUP], Kirsten Obernier[SUP] 1 [/SUP], Jacqueline M Fabius[SUP] 1 [/SUP], Margaret Soucheray[SUP] 1 [/SUP], Lisa Miorin[SUP] 4 [/SUP], Elena Moreno[SUP] 4 [/SUP], Cassandra Koh[SUP] 3 [/SUP], Quang Dinh Tran[SUP] 3 [/SUP], Alexandra Hardy[SUP] 3 [/SUP], R?my Robinot[SUP] 7 [/SUP], Thomas Vallet[SUP] 3 [/SUP], Benjamin E Nilsson-Payant[SUP] 8 [/SUP], Claudia Hernandez-Armenta[SUP] 2 [/SUP], Alistair Dunham[SUP] 2 [/SUP], Sebastian Weigang[SUP] 9 [/SUP], Julian Knerr[SUP] 6 [/SUP], Maya Modak[SUP] 1 [/SUP], Diego Quintero[SUP] 1 [/SUP], Yuan Zhou[SUP] 1 [/SUP], Aurelien Dugourd[SUP] 10 [/SUP], Alberto Valdeolivas[SUP] 10 [/SUP], Trupti Patil[SUP] 1 [/SUP], Qiongyu Li[SUP] 1 [/SUP], Ruth H?ttenhain[SUP] 1 [/SUP], Merve Cakir[SUP] 1 [/SUP], Monita Muralidharan[SUP] 1 [/SUP], Minkyu Kim[SUP] 1 [/SUP], Gwendolyn Jang[SUP] 1 [/SUP], Beril Tutuncuoglu[SUP] 1 [/SUP], Joseph Hiatt[SUP] 1 [/SUP], Jeffrey Z Guo[SUP] 1 [/SUP], Jiewei Xu[SUP] 1 [/SUP], Sophia Bouhaddou[SUP] 11 [/SUP], Christopher J P Mathy[SUP] 12 [/SUP], Anna Gaulton[SUP] 2 [/SUP], Emma J Manners[SUP] 2 [/SUP], Eloy F?lix[SUP] 2 [/SUP], Ying Shi[SUP] 5 [/SUP], Marisa Goff[SUP] 8 [/SUP], Jean K Lim[SUP] 8 [/SUP], Timothy McBride[SUP] 13 [/SUP], Michael C O'Neal[SUP] 13 [/SUP], Yiming Cai[SUP] 13 [/SUP], Jason C J Chang[SUP] 13 [/SUP], David J Broadhurst[SUP] 13 [/SUP], Saker Klippsten[SUP] 13 [/SUP], Emmie De Wit[SUP] 14 [/SUP], Andrew R Leach[SUP] 2 [/SUP], Tanja Kortemme[SUP] 12 [/SUP], Brian Shoichet[SUP] 15 [/SUP], Melanie Ott[SUP] 16 [/SUP], Julio Saez-Rodriguez[SUP] 9 [/SUP], Benjamin R tenOever[SUP] 8 [/SUP], R Dyche Mullins[SUP] 17 [/SUP], Elizabeth R Fischer[SUP] 14 [/SUP], Georg Kochs[SUP] 18 [/SUP], Robert Grosse[SUP] 19 [/SUP], Adolfo Garc?a-Sastre[SUP] 20 [/SUP], Marco Vignuzzi[SUP] 21 [/SUP], Jeffery R Johnson[SUP] 22 [/SUP], Kevan M Shokat[SUP] 23 [/SUP], Danielle L Swaney[SUP] 24 [/SUP], Pedro Beltrao[SUP] 25 [/SUP], Nevan J Krogan[SUP] 26 [/SUP]
Affiliations
- PMID: 32645325
- DOI: 10.1016/j.cell.2020.06.034
Abstract
The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.
Keywords: AXL; CDK; MAPK; PIKFYVE; SARS-CoV-2; antiviral; casein kinase II; mass spectrometry; p38; phosphoproteomics.