tetano
Editor, Senior Moderator
Cells
. 2023 Nov 23;12(23):2694.
doi: 10.3390/cells12232694. Calreticulin Regulates SARS-CoV-2 Spike Protein Turnover and Modulates SARS-CoV-2 Infectivity
Nader Rahimi[SUP] 1 [/SUP], Mitchell R White[SUP] 2 3 [/SUP], Razie Amraei[SUP] 1 [/SUP], Saran Lotfollahzadeh[SUP] 4 [/SUP], Chaoshuang Xia[SUP] 5 [/SUP], Marek Michalak[SUP] 6 [/SUP], Catherine E Costello[SUP] 5 [/SUP], Elke Mühlberger[SUP] 2 3 [/SUP]
Affiliations
Cardiovascular complications are major clinical hallmarks of acute and post-acute coronavirus disease 2019 (COVID-19). However, the mechanistic details of SARS-CoV-2 infectivity of endothelial cells remain largely unknown. Here, we demonstrate that the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein shares a similarity with the proline-rich binding ena/VASP homology (EVH1) domain and identified the endoplasmic reticulum (ER) resident calreticulin (CALR) as an S-RBD interacting protein. Our biochemical analysis showed that CALR, via its proline-rich (P) domain, interacts with S-RBD and modulates proteostasis of the S protein. Treatment of cells with the proteasomal inhibitor bortezomib increased the expression of the S protein independent of CALR, whereas the lysosomal/autophagy inhibitor bafilomycin 1A, which interferes with the acidification of lysosome, selectively augmented the S protein levels in a CALR-dependent manner. More importantly, the shRNA-mediated knockdown of CALR increased SARS-CoV-2 infection and impaired calcium homeostasis of human endothelial cells. This study provides new insight into the infectivity of SARS-CoV-2, calcium hemostasis, and the role of CALR in the ER-lysosome-dependent proteolysis of the spike protein, which could be associated with cardiovascular complications in COVID-19 patients.
Keywords: COVID-19; S-RBD; SARS-CoV-2; calreticulin; endothelial cells; intracellular calcium homeostasis; spike protein.
. 2023 Nov 23;12(23):2694.
doi: 10.3390/cells12232694. Calreticulin Regulates SARS-CoV-2 Spike Protein Turnover and Modulates SARS-CoV-2 Infectivity
Nader Rahimi[SUP] 1 [/SUP], Mitchell R White[SUP] 2 3 [/SUP], Razie Amraei[SUP] 1 [/SUP], Saran Lotfollahzadeh[SUP] 4 [/SUP], Chaoshuang Xia[SUP] 5 [/SUP], Marek Michalak[SUP] 6 [/SUP], Catherine E Costello[SUP] 5 [/SUP], Elke Mühlberger[SUP] 2 3 [/SUP]
Affiliations
- PMID: 38067122
- PMCID: PMC10705507
- DOI: 10.3390/cells12232694
Cardiovascular complications are major clinical hallmarks of acute and post-acute coronavirus disease 2019 (COVID-19). However, the mechanistic details of SARS-CoV-2 infectivity of endothelial cells remain largely unknown. Here, we demonstrate that the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein shares a similarity with the proline-rich binding ena/VASP homology (EVH1) domain and identified the endoplasmic reticulum (ER) resident calreticulin (CALR) as an S-RBD interacting protein. Our biochemical analysis showed that CALR, via its proline-rich (P) domain, interacts with S-RBD and modulates proteostasis of the S protein. Treatment of cells with the proteasomal inhibitor bortezomib increased the expression of the S protein independent of CALR, whereas the lysosomal/autophagy inhibitor bafilomycin 1A, which interferes with the acidification of lysosome, selectively augmented the S protein levels in a CALR-dependent manner. More importantly, the shRNA-mediated knockdown of CALR increased SARS-CoV-2 infection and impaired calcium homeostasis of human endothelial cells. This study provides new insight into the infectivity of SARS-CoV-2, calcium hemostasis, and the role of CALR in the ER-lysosome-dependent proteolysis of the spike protein, which could be associated with cardiovascular complications in COVID-19 patients.
Keywords: COVID-19; S-RBD; SARS-CoV-2; calreticulin; endothelial cells; intracellular calcium homeostasis; spike protein.