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Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1

Dengue virus (DENV) infection is a significant public health threat in tropical and subtropical regions; however, there is no specific antiviral drug. Accumulated studies have revealed that DENV infection induces several cellular responses, including autophagy and apoptosis. The crosstalk between au...

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Autores principales: Lu, Zi-Yi, Cheng, Miao-Huei, Yu, Chia-Yi, Lin, Yee-Shin, Yeh, Trai-Ming, Chen, Chia-Ling, Chen, Chien-Chin, Wan, Shu-Wen, Chang, Chih-Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766445/
https://www.ncbi.nlm.nih.gov/pubmed/33352639
http://dx.doi.org/10.3390/ijms21249702
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author Lu, Zi-Yi
Cheng, Miao-Huei
Yu, Chia-Yi
Lin, Yee-Shin
Yeh, Trai-Ming
Chen, Chia-Ling
Chen, Chien-Chin
Wan, Shu-Wen
Chang, Chih-Peng
author_facet Lu, Zi-Yi
Cheng, Miao-Huei
Yu, Chia-Yi
Lin, Yee-Shin
Yeh, Trai-Ming
Chen, Chia-Ling
Chen, Chien-Chin
Wan, Shu-Wen
Chang, Chih-Peng
author_sort Lu, Zi-Yi
collection PubMed
description Dengue virus (DENV) infection is a significant public health threat in tropical and subtropical regions; however, there is no specific antiviral drug. Accumulated studies have revealed that DENV infection induces several cellular responses, including autophagy and apoptosis. The crosstalk between autophagy and apoptosis is associated with the interactions among components of these two pathways, such as apoptotic caspase-mediated cleavage of autophagy-related proteins. Here, we show that DENV-induced autophagy inhibits early cell apoptosis and hence enhances DENV replication. Later, the apoptotic activities are elevated to suppress autophagy through cleavage of Beclin-1, an essential autophagy-related protein. Inhibition of cleavage of Beclin-1 by a pan-caspase inhibitor, Z-VAD, increases both autophagy and viral replication. Regarding the mechanism, we further found that DENV nonstructural protein 1 (NS1) is able to interact with Beclin-1 during DENV infection. The interaction between Beclin-1 and NS1 attenuates Beclin-1 cleavage and facilitates autophagy to prevent cell apoptosis. Our study suggests a novel mechanism whereby NS1 preserves Beclin-1 for maintaining autophagy to antagonize early cell apoptosis; however, elevated caspases trigger apoptosis by degrading Beclin-1 in the late stage of infection. These findings suggest implications for anti-DENV drug design.
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spelling pubmed-77664452020-12-28 Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1 Lu, Zi-Yi Cheng, Miao-Huei Yu, Chia-Yi Lin, Yee-Shin Yeh, Trai-Ming Chen, Chia-Ling Chen, Chien-Chin Wan, Shu-Wen Chang, Chih-Peng Int J Mol Sci Article Dengue virus (DENV) infection is a significant public health threat in tropical and subtropical regions; however, there is no specific antiviral drug. Accumulated studies have revealed that DENV infection induces several cellular responses, including autophagy and apoptosis. The crosstalk between autophagy and apoptosis is associated with the interactions among components of these two pathways, such as apoptotic caspase-mediated cleavage of autophagy-related proteins. Here, we show that DENV-induced autophagy inhibits early cell apoptosis and hence enhances DENV replication. Later, the apoptotic activities are elevated to suppress autophagy through cleavage of Beclin-1, an essential autophagy-related protein. Inhibition of cleavage of Beclin-1 by a pan-caspase inhibitor, Z-VAD, increases both autophagy and viral replication. Regarding the mechanism, we further found that DENV nonstructural protein 1 (NS1) is able to interact with Beclin-1 during DENV infection. The interaction between Beclin-1 and NS1 attenuates Beclin-1 cleavage and facilitates autophagy to prevent cell apoptosis. Our study suggests a novel mechanism whereby NS1 preserves Beclin-1 for maintaining autophagy to antagonize early cell apoptosis; however, elevated caspases trigger apoptosis by degrading Beclin-1 in the late stage of infection. These findings suggest implications for anti-DENV drug design. MDPI 2020-12-19 /pmc/articles/PMC7766445/ /pubmed/33352639 http://dx.doi.org/10.3390/ijms21249702 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lu, Zi-Yi
Cheng, Miao-Huei
Yu, Chia-Yi
Lin, Yee-Shin
Yeh, Trai-Ming
Chen, Chia-Ling
Chen, Chien-Chin
Wan, Shu-Wen
Chang, Chih-Peng
Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1
title Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1
title_full Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1
title_fullStr Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1
title_full_unstemmed Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1
title_short Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1
title_sort dengue nonstructural protein 1 maintains autophagy through retarding caspase-mediated cleavage of beclin-1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766445/
https://www.ncbi.nlm.nih.gov/pubmed/33352639
http://dx.doi.org/10.3390/ijms21249702
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