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Protein Arginylation Is Regulated during SARS-CoV-2 Infection
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964439/ https://www.ncbi.nlm.nih.gov/pubmed/36851505 http://dx.doi.org/10.3390/v15020290 |
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author | Macedo-da-Silva, Janaina Rosa-Fernandes, Livia Gomes, Vinicius de Morais Santiago, Veronica Feijoli Santos, Deivid Martins Molnar, Catarina Maria Stanischesk Barboza, Bruno Rafael de Souza, Edmarcia Elisa Marques, Rodolfo Ferreira Boscardin, Silvia Beatriz Durigon, Edison Luiz Marinho, Claudio Romero Farias Wrenger, Carsten Marie, Suely Kazue Nagahashi Palmisano, Giuseppe |
author_facet | Macedo-da-Silva, Janaina Rosa-Fernandes, Livia Gomes, Vinicius de Morais Santiago, Veronica Feijoli Santos, Deivid Martins Molnar, Catarina Maria Stanischesk Barboza, Bruno Rafael de Souza, Edmarcia Elisa Marques, Rodolfo Ferreira Boscardin, Silvia Beatriz Durigon, Edison Luiz Marinho, Claudio Romero Farias Wrenger, Carsten Marie, Suely Kazue Nagahashi Palmisano, Giuseppe |
author_sort | Macedo-da-Silva, Janaina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9964439 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99644392023-02-26 Protein Arginylation Is Regulated during SARS-CoV-2 Infection Macedo-da-Silva, Janaina Rosa-Fernandes, Livia Gomes, Vinicius de Morais Santiago, Veronica Feijoli Santos, Deivid Martins Molnar, Catarina Maria Stanischesk Barboza, Bruno Rafael de Souza, Edmarcia Elisa Marques, Rodolfo Ferreira Boscardin, Silvia Beatriz Durigon, Edison Luiz Marinho, Claudio Romero Farias Wrenger, Carsten Marie, Suely Kazue Nagahashi Palmisano, Giuseppe Viruses Article 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. MDPI 2023-01-19 /pmc/articles/PMC9964439/ /pubmed/36851505 http://dx.doi.org/10.3390/v15020290 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Macedo-da-Silva, Janaina Rosa-Fernandes, Livia Gomes, Vinicius de Morais Santiago, Veronica Feijoli Santos, Deivid Martins Molnar, Catarina Maria Stanischesk Barboza, Bruno Rafael de Souza, Edmarcia Elisa Marques, Rodolfo Ferreira Boscardin, Silvia Beatriz Durigon, Edison Luiz Marinho, Claudio Romero Farias Wrenger, Carsten Marie, Suely Kazue Nagahashi Palmisano, Giuseppe Protein Arginylation Is Regulated during SARS-CoV-2 Infection |
title | Protein Arginylation Is Regulated during SARS-CoV-2 Infection |
title_full | Protein Arginylation Is Regulated during SARS-CoV-2 Infection |
title_fullStr | Protein Arginylation Is Regulated during SARS-CoV-2 Infection |
title_full_unstemmed | Protein Arginylation Is Regulated during SARS-CoV-2 Infection |
title_short | Protein Arginylation Is Regulated during SARS-CoV-2 Infection |
title_sort | protein arginylation is regulated during sars-cov-2 infection |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964439/ https://www.ncbi.nlm.nih.gov/pubmed/36851505 http://dx.doi.org/10.3390/v15020290 |
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