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PERK Is Critical for Alphavirus Nonstructural Protein Translation

Venezuelan equine encephalitis virus (VEEV) is an alphavirus that causes encephalitis. Previous work indicated that VEEV infection induced early growth response 1 (EGR1) expression, leading to cell death via the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of the unfolded prot...

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Autores principales: Dahal, Bibha, Lehman, Caitlin W., Akhrymuk, Ivan, Bracci, Nicole R., Panny, Lauren, Barrera, Michael D., Bhalla, Nishank, Jacobs, Jonathan L., Dinman, Jonathan D., Kehn-Hall, Kylene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151226/
https://www.ncbi.nlm.nih.gov/pubmed/34065980
http://dx.doi.org/10.3390/v13050892
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author Dahal, Bibha
Lehman, Caitlin W.
Akhrymuk, Ivan
Bracci, Nicole R.
Panny, Lauren
Barrera, Michael D.
Bhalla, Nishank
Jacobs, Jonathan L.
Dinman, Jonathan D.
Kehn-Hall, Kylene
author_facet Dahal, Bibha
Lehman, Caitlin W.
Akhrymuk, Ivan
Bracci, Nicole R.
Panny, Lauren
Barrera, Michael D.
Bhalla, Nishank
Jacobs, Jonathan L.
Dinman, Jonathan D.
Kehn-Hall, Kylene
author_sort Dahal, Bibha
collection PubMed
description Venezuelan equine encephalitis virus (VEEV) is an alphavirus that causes encephalitis. Previous work indicated that VEEV infection induced early growth response 1 (EGR1) expression, leading to cell death via the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of the unfolded protein response (UPR) pathway. Loss of PERK prevented EGR1 induction and decreased VEEV-induced death. The results presented within show that loss of PERK in human primary astrocytes dramatically reduced VEEV and eastern equine encephalitis virus (EEEV) infectious titers by 4–5 log(10). Loss of PERK also suppressed VEEV replication in primary human pericytes and human umbilical vein endothelial cells, but it had no impact on VEEV replication in transformed U87MG and 293T cells. A significant reduction in VEEV RNA levels was observed as early as 3 h post-infection, but viral entry assays indicated that the loss of PERK minimally impacted VEEV entry. In contrast, the loss of PERK resulted in a dramatic reduction in viral nonstructural protein translation and negative-strand viral RNA production. The loss of PERK also reduced the production of Rift Valley fever virus and Zika virus infectious titers. These data indicate that PERK is an essential factor for the translation of alphavirus nonstructural proteins and impacts multiple RNA viruses, making it an exciting target for antiviral development.
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spelling pubmed-81512262021-05-27 PERK Is Critical for Alphavirus Nonstructural Protein Translation Dahal, Bibha Lehman, Caitlin W. Akhrymuk, Ivan Bracci, Nicole R. Panny, Lauren Barrera, Michael D. Bhalla, Nishank Jacobs, Jonathan L. Dinman, Jonathan D. Kehn-Hall, Kylene Viruses Article Venezuelan equine encephalitis virus (VEEV) is an alphavirus that causes encephalitis. Previous work indicated that VEEV infection induced early growth response 1 (EGR1) expression, leading to cell death via the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of the unfolded protein response (UPR) pathway. Loss of PERK prevented EGR1 induction and decreased VEEV-induced death. The results presented within show that loss of PERK in human primary astrocytes dramatically reduced VEEV and eastern equine encephalitis virus (EEEV) infectious titers by 4–5 log(10). Loss of PERK also suppressed VEEV replication in primary human pericytes and human umbilical vein endothelial cells, but it had no impact on VEEV replication in transformed U87MG and 293T cells. A significant reduction in VEEV RNA levels was observed as early as 3 h post-infection, but viral entry assays indicated that the loss of PERK minimally impacted VEEV entry. In contrast, the loss of PERK resulted in a dramatic reduction in viral nonstructural protein translation and negative-strand viral RNA production. The loss of PERK also reduced the production of Rift Valley fever virus and Zika virus infectious titers. These data indicate that PERK is an essential factor for the translation of alphavirus nonstructural proteins and impacts multiple RNA viruses, making it an exciting target for antiviral development. MDPI 2021-05-12 /pmc/articles/PMC8151226/ /pubmed/34065980 http://dx.doi.org/10.3390/v13050892 Text en © 2021 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
Dahal, Bibha
Lehman, Caitlin W.
Akhrymuk, Ivan
Bracci, Nicole R.
Panny, Lauren
Barrera, Michael D.
Bhalla, Nishank
Jacobs, Jonathan L.
Dinman, Jonathan D.
Kehn-Hall, Kylene
PERK Is Critical for Alphavirus Nonstructural Protein Translation
title PERK Is Critical for Alphavirus Nonstructural Protein Translation
title_full PERK Is Critical for Alphavirus Nonstructural Protein Translation
title_fullStr PERK Is Critical for Alphavirus Nonstructural Protein Translation
title_full_unstemmed PERK Is Critical for Alphavirus Nonstructural Protein Translation
title_short PERK Is Critical for Alphavirus Nonstructural Protein Translation
title_sort perk is critical for alphavirus nonstructural protein translation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151226/
https://www.ncbi.nlm.nih.gov/pubmed/34065980
http://dx.doi.org/10.3390/v13050892
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