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Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways
Despite autophagy’s pivotal role in the replication of viruses such as duck Tembusu virus (DTMUV), which has caused massive economic losses to the poultry industry in the world, the specific relationships between DTMUV and cellular autophagy remain largely unknown. In response, we investigated the i...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851233/ https://www.ncbi.nlm.nih.gov/pubmed/35185869 http://dx.doi.org/10.3389/fimmu.2022.746890 |
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author | Zhao, Jun Zhang, Tingting Chen, Guomin Geng, Ningwei Guo, Zhiyun Cao, Shengliang Yang, Yudong Liu, Kuihao Wang, Siqi Zhao, Yiran Meng, Fanliang Liu, Sidang Jiang, Meijie Li, Ning |
author_facet | Zhao, Jun Zhang, Tingting Chen, Guomin Geng, Ningwei Guo, Zhiyun Cao, Shengliang Yang, Yudong Liu, Kuihao Wang, Siqi Zhao, Yiran Meng, Fanliang Liu, Sidang Jiang, Meijie Li, Ning |
author_sort | Zhao, Jun |
collection | PubMed |
description | Despite autophagy’s pivotal role in the replication of viruses such as duck Tembusu virus (DTMUV), which has caused massive economic losses to the poultry industry in the world, the specific relationships between DTMUV and cellular autophagy remain largely unknown. In response, we investigated the interactions between autophagy and DTMUV, the effects of the structural and non-structural proteins of DTMUV on autophagy, and the autophagy-related signaling pathways induced by DTMUV. Among the results, DTMUV increased the autophagy flux in duck embryo fibroblasts (DEF) and BHK-21 cells, while autophagy facilitated viral replication. After we pharmacologically induced autophagy with rapamycin (RAPA), the replication of DTMUV increased by 15.23-fold compared with the control group of DEF cells. To identify which DTMUV protein primarily induced autophagy, all three structural proteins and seven non-structural proteins of DTMUV were transfected into cells, and the results showed that non-structural protein 3 (NS3) induced significant autophagy in DEF cells. By means of Western blot, immunofluorescence, and transmission electron microscopy, we confirmed that NS3 protein could significantly induce autophagy and autophagy flux. Furthermore, we showed that NS3 induced autophagy in DEF cells through extracellular signal-regulated kinase 2 (ERK2) and phosphatidylinositol-3-kinase (PI3K)/AKT and the mammalian target of rapamycin (mTOR) signaling pathways using specific inhibitors and RNA interference assays. Finally, autophagy induced by NS3 promoted DTMUV replication. These results provide novel insight into the relationship between DTMUV and autophagy, broadening the current understanding of the molecular pathogenesis of DTMUV. |
format | Online Article Text |
id | pubmed-8851233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88512332022-02-18 Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways Zhao, Jun Zhang, Tingting Chen, Guomin Geng, Ningwei Guo, Zhiyun Cao, Shengliang Yang, Yudong Liu, Kuihao Wang, Siqi Zhao, Yiran Meng, Fanliang Liu, Sidang Jiang, Meijie Li, Ning Front Immunol Immunology Despite autophagy’s pivotal role in the replication of viruses such as duck Tembusu virus (DTMUV), which has caused massive economic losses to the poultry industry in the world, the specific relationships between DTMUV and cellular autophagy remain largely unknown. In response, we investigated the interactions between autophagy and DTMUV, the effects of the structural and non-structural proteins of DTMUV on autophagy, and the autophagy-related signaling pathways induced by DTMUV. Among the results, DTMUV increased the autophagy flux in duck embryo fibroblasts (DEF) and BHK-21 cells, while autophagy facilitated viral replication. After we pharmacologically induced autophagy with rapamycin (RAPA), the replication of DTMUV increased by 15.23-fold compared with the control group of DEF cells. To identify which DTMUV protein primarily induced autophagy, all three structural proteins and seven non-structural proteins of DTMUV were transfected into cells, and the results showed that non-structural protein 3 (NS3) induced significant autophagy in DEF cells. By means of Western blot, immunofluorescence, and transmission electron microscopy, we confirmed that NS3 protein could significantly induce autophagy and autophagy flux. Furthermore, we showed that NS3 induced autophagy in DEF cells through extracellular signal-regulated kinase 2 (ERK2) and phosphatidylinositol-3-kinase (PI3K)/AKT and the mammalian target of rapamycin (mTOR) signaling pathways using specific inhibitors and RNA interference assays. Finally, autophagy induced by NS3 promoted DTMUV replication. These results provide novel insight into the relationship between DTMUV and autophagy, broadening the current understanding of the molecular pathogenesis of DTMUV. Frontiers Media S.A. 2022-02-03 /pmc/articles/PMC8851233/ /pubmed/35185869 http://dx.doi.org/10.3389/fimmu.2022.746890 Text en Copyright © 2022 Zhao, Zhang, Chen, Geng, Guo, Cao, Yang, Liu, Wang, Zhao, Meng, Liu, Jiang and Li https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Zhao, Jun Zhang, Tingting Chen, Guomin Geng, Ningwei Guo, Zhiyun Cao, Shengliang Yang, Yudong Liu, Kuihao Wang, Siqi Zhao, Yiran Meng, Fanliang Liu, Sidang Jiang, Meijie Li, Ning Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways |
title | Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways |
title_full | Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways |
title_fullStr | Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways |
title_full_unstemmed | Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways |
title_short | Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways |
title_sort | non-structural protein 3 of duck tembusu virus induces autophagy via the erk and pi3k–akt–mtor signaling pathways |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851233/ https://www.ncbi.nlm.nih.gov/pubmed/35185869 http://dx.doi.org/10.3389/fimmu.2022.746890 |
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