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The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation

The unfolded protein response (UPR) is an intracellular signaling pathway essential for alleviating the endoplasmic reticulum (ER) stress. To support the productive infection, many viruses are known to use different strategies to manipulate the UPR signaling network. However, it remains largely uncl...

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Autores principales: Chen, Lee-Wen, Wang, Shie-Shan, Hung, Chien-Hui, Hung, Ya-Hui, Lin, Chun-Liang, Chang, Pey-Jium
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070695/
https://www.ncbi.nlm.nih.gov/pubmed/33919712
http://dx.doi.org/10.3390/ijms22084024
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author Chen, Lee-Wen
Wang, Shie-Shan
Hung, Chien-Hui
Hung, Ya-Hui
Lin, Chun-Liang
Chang, Pey-Jium
author_facet Chen, Lee-Wen
Wang, Shie-Shan
Hung, Chien-Hui
Hung, Ya-Hui
Lin, Chun-Liang
Chang, Pey-Jium
author_sort Chen, Lee-Wen
collection PubMed
description The unfolded protein response (UPR) is an intracellular signaling pathway essential for alleviating the endoplasmic reticulum (ER) stress. To support the productive infection, many viruses are known to use different strategies to manipulate the UPR signaling network. However, it remains largely unclear whether the UPR signaling pathways are modulated in the lytic cycle of Epstein-Barr virus (EBV), a widely distributed human pathogen. Herein, we show that the expression of GRP78, a central UPR regulator, is up-regulated during the EBV lytic cycle. Our data further revealed that knockdown of GRP78 in EBV-infected cell lines did not substantially affect lytic gene expression; however, GRP78 knockdown in these cells markedly reduced the production of virus particles. Importantly, we identified that the early lytic protein BMLF1 is the key regulator critically contributing to the activation of the grp78 gene promoter. Mechanistically, we found that BMLF1 can trigger the proteolytic cleavage and activation of the UPR senor ATF6, which then transcriptionally activates the grp78 promoter through the ER stress response elements. Our findings therefore provide evidence for the connection between the EBV lytic cycle and the UPR, and implicate that the BMLF1-mediated ATF6 activation may play critical roles in EBV lytic replication.
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spelling pubmed-80706952021-04-26 The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation Chen, Lee-Wen Wang, Shie-Shan Hung, Chien-Hui Hung, Ya-Hui Lin, Chun-Liang Chang, Pey-Jium Int J Mol Sci Article The unfolded protein response (UPR) is an intracellular signaling pathway essential for alleviating the endoplasmic reticulum (ER) stress. To support the productive infection, many viruses are known to use different strategies to manipulate the UPR signaling network. However, it remains largely unclear whether the UPR signaling pathways are modulated in the lytic cycle of Epstein-Barr virus (EBV), a widely distributed human pathogen. Herein, we show that the expression of GRP78, a central UPR regulator, is up-regulated during the EBV lytic cycle. Our data further revealed that knockdown of GRP78 in EBV-infected cell lines did not substantially affect lytic gene expression; however, GRP78 knockdown in these cells markedly reduced the production of virus particles. Importantly, we identified that the early lytic protein BMLF1 is the key regulator critically contributing to the activation of the grp78 gene promoter. Mechanistically, we found that BMLF1 can trigger the proteolytic cleavage and activation of the UPR senor ATF6, which then transcriptionally activates the grp78 promoter through the ER stress response elements. Our findings therefore provide evidence for the connection between the EBV lytic cycle and the UPR, and implicate that the BMLF1-mediated ATF6 activation may play critical roles in EBV lytic replication. MDPI 2021-04-14 /pmc/articles/PMC8070695/ /pubmed/33919712 http://dx.doi.org/10.3390/ijms22084024 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
Chen, Lee-Wen
Wang, Shie-Shan
Hung, Chien-Hui
Hung, Ya-Hui
Lin, Chun-Liang
Chang, Pey-Jium
The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation
title The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation
title_full The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation
title_fullStr The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation
title_full_unstemmed The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation
title_short The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation
title_sort epstein-barr virus lytic protein bmlf1 induces upregulation of grp78 expression through atf6 activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070695/
https://www.ncbi.nlm.nih.gov/pubmed/33919712
http://dx.doi.org/10.3390/ijms22084024
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