ATP2B1 is a known regulator of calcium (Ca2+) cellular export and homeostasis. Diminished levels of intracellular Ca2+ content have been suggested to impair SARS-CoV-2 replication. Here, we demonstrate that a nontoxic caloxin-derivative compound (PI-7) reduces intracellular Ca2+ levels and impairs SARS-CoV-2 infection. Furthermore, a rare homozygous intronic variant of ATP2B1 is shown to be associated with the severity of COVID-19. The mechanism of action during SARS-CoV-2 infection involves the PI3K/Akt signaling pathway activation, inactivation of FOXO3 transcription factor function, and subsequent transcriptional inhibition of the membrane and reticulum Ca2+ pumps ATP2B1 and ATP2A1, respectively. The pharmacological action of compound PI-7 on sustaining both ATP2B1 and ATP2A1 expression reduces the intracellular cytoplasmic Ca2+ pool and thus negatively influences SARS-CoV-2 replication and propagation. As compound PI-7 lacks toxicity in vitro, its prophylactic use as a therapeutic agent against COVID-19 is envisioned here.

Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication / de Antonellis, Pasqualino; Ferrucci, Veronica; Miceli, Marco; Bibbo, Francesca; Asadzadeh, Fatemeh; Gorini, Francesca; Mattivi, Alessia; Boccia, Angelo; Russo, Roberta; Andolfo, Immacolata; Lasorsa, Vito Alessandro; Cantalupo, Sueva; Fusco, Giovanna; Viscardi, Maurizio; Brandi, Sergio; Cerino, Pellegrino; Monaco, Vittoria; Choi, Dong-Rac; Cheong, Jae-Ho; Iolascon, Achille; Amente, Stefano; Monti, Maria; Fava, Luca; Capasso, Mario; Kim, Hong-Yeoul; Zollo, Massimo. - In: EMBO REPORTS. - ISSN 1469-3178. - 2024, 25:7(2024), pp. 2974-3007. [10.1038/s44319-024-00164-z]

Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication

Mattivi, Alessia;Fava, Luca;
2024-01-01

Abstract

ATP2B1 is a known regulator of calcium (Ca2+) cellular export and homeostasis. Diminished levels of intracellular Ca2+ content have been suggested to impair SARS-CoV-2 replication. Here, we demonstrate that a nontoxic caloxin-derivative compound (PI-7) reduces intracellular Ca2+ levels and impairs SARS-CoV-2 infection. Furthermore, a rare homozygous intronic variant of ATP2B1 is shown to be associated with the severity of COVID-19. The mechanism of action during SARS-CoV-2 infection involves the PI3K/Akt signaling pathway activation, inactivation of FOXO3 transcription factor function, and subsequent transcriptional inhibition of the membrane and reticulum Ca2+ pumps ATP2B1 and ATP2A1, respectively. The pharmacological action of compound PI-7 on sustaining both ATP2B1 and ATP2A1 expression reduces the intracellular cytoplasmic Ca2+ pool and thus negatively influences SARS-CoV-2 replication and propagation. As compound PI-7 lacks toxicity in vitro, its prophylactic use as a therapeutic agent against COVID-19 is envisioned here.
2024
7
de Antonellis, Pasqualino; Ferrucci, Veronica; Miceli, Marco; Bibbo, Francesca; Asadzadeh, Fatemeh; Gorini, Francesca; Mattivi, Alessia; Boccia, Angel...espandi
Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication / de Antonellis, Pasqualino; Ferrucci, Veronica; Miceli, Marco; Bibbo, Francesca; Asadzadeh, Fatemeh; Gorini, Francesca; Mattivi, Alessia; Boccia, Angelo; Russo, Roberta; Andolfo, Immacolata; Lasorsa, Vito Alessandro; Cantalupo, Sueva; Fusco, Giovanna; Viscardi, Maurizio; Brandi, Sergio; Cerino, Pellegrino; Monaco, Vittoria; Choi, Dong-Rac; Cheong, Jae-Ho; Iolascon, Achille; Amente, Stefano; Monti, Maria; Fava, Luca; Capasso, Mario; Kim, Hong-Yeoul; Zollo, Massimo. - In: EMBO REPORTS. - ISSN 1469-3178. - 2024, 25:7(2024), pp. 2974-3007. [10.1038/s44319-024-00164-z]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/418131
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