Protein Arginylation Is Regulated during SARS-CoV-2 Infection

Autor: Janaina Macedo-da-Silva, Livia Rosa-Fernandes, Vinicius de Morais Gomes, Veronica Feijoli Santiago, Deivid Martins Santos, Catarina Maria Stanischesk Molnar, Bruno Rafael Barboza, Edmarcia Elisa de Souza, Rodolfo Ferreira Marques, Silvia Beatriz Boscardin, Edison Luiz Durigon, Claudio Romero Farias Marinho, Carsten Wrenger, Suely Kazue Nagahashi Marie, Giuseppe Palmisano
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Viruses, Vol 15, Iss 2, p 290 (2023)
Druh dokumentu: article
ISSN: 15020290
1999-4915
DOI: 10.3390/v15020290
Popis: Background: In 2019, the world witnessed the onset of an unprecedented pandemic. By February 2022, the infection by SARS-CoV-2 has already been responsible for the death of more than 5 million people worldwide. Recently, we and other groups discovered that SARS-CoV-2 infection induces ER stress and activation of the unfolded protein response (UPR) pathway. Degradation of misfolded/unfolded proteins is an essential element of proteostasis and occurs mainly in lysosomes or proteasomes. The N-terminal arginylation of proteins is characterized as an inducer of ubiquitination and proteasomal degradation by the N-degron pathway. Results: The role of protein arginylation during SARS-CoV-2 infection was elucidated. Protein arginylation was studied in Vero CCL-81, macrophage-like THP1, and Calu-3 cells infected at different times. A reanalysis of in vivo and in vitro public omics data combined with immunoblotting was performed to measure levels of arginyl-tRNA-protein transferase (ATE1) and its substrates. Dysregulation of the N-degron pathway was specifically identified during coronavirus infections compared to other respiratory viruses. We demonstrated that during SARS-CoV-2 infection, there is an increase in ATE1 expression in Calu-3 and Vero CCL-81 cells. On the other hand, infected macrophages showed no enzyme regulation. ATE1 and protein arginylation was variant-dependent, as shown using P1 and P2 viral variants and HEK 293T cells transfection with the spike protein and receptor-binding domains (RBD). In addition, we report that ATE1 inhibitors, tannic acid and merbromine (MER) reduce viral load. This finding was confirmed in ATE1-silenced cells. Conclusions: We demonstrate that ATE1 is increased during SARS-CoV-2 infection and its inhibition has potential therapeutic value.
Databáze: Directory of Open Access Journals
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