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Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection

The group of enteroviruses contains many important pathogens for humans, including poliovirus, coxsackievirus, rhinovirus, as well as newly emerging global health threats such as EV-A71 and EV-D68. Here, we describe an unbiased, system-wide and time-resolved analysis of the proteome and phosphoprote...

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Autores principales: Giansanti, Piero, Strating, Jeroen R. P. M., Defourny, Kyra A. Y., Cesonyte, Ieva, Bottino, Alexia M. S., Post, Harm, Viktorova, Ekaterina G., Ho, Vien Quang Tri, Langereis, Martijn A., Belov, George A., Nolte-‘t Hoen, Esther N. M., Heck, Albert J. R., van Kuppeveld, Frank J. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455705/
https://www.ncbi.nlm.nih.gov/pubmed/32859902
http://dx.doi.org/10.1038/s41467-020-18168-3
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author Giansanti, Piero
Strating, Jeroen R. P. M.
Defourny, Kyra A. Y.
Cesonyte, Ieva
Bottino, Alexia M. S.
Post, Harm
Viktorova, Ekaterina G.
Ho, Vien Quang Tri
Langereis, Martijn A.
Belov, George A.
Nolte-‘t Hoen, Esther N. M.
Heck, Albert J. R.
van Kuppeveld, Frank J. M.
author_facet Giansanti, Piero
Strating, Jeroen R. P. M.
Defourny, Kyra A. Y.
Cesonyte, Ieva
Bottino, Alexia M. S.
Post, Harm
Viktorova, Ekaterina G.
Ho, Vien Quang Tri
Langereis, Martijn A.
Belov, George A.
Nolte-‘t Hoen, Esther N. M.
Heck, Albert J. R.
van Kuppeveld, Frank J. M.
author_sort Giansanti, Piero
collection PubMed
description The group of enteroviruses contains many important pathogens for humans, including poliovirus, coxsackievirus, rhinovirus, as well as newly emerging global health threats such as EV-A71 and EV-D68. Here, we describe an unbiased, system-wide and time-resolved analysis of the proteome and phosphoproteome of human cells infected with coxsackievirus B3. Of the ~3,200 proteins quantified throughout the time course, a large amount (~25%) shows a significant change, with the majority being downregulated. We find ~85% of the detected phosphosites to be significantly regulated, implying that most changes occur at the post-translational level. Kinase-motif analysis reveals temporal activation patterns of certain protein kinases, with several CDKs/MAPKs immediately active upon the infection, and basophilic kinases, ATM, and ATR engaging later. Through bioinformatics analysis and dedicated experiments, we identify mTORC1 signalling as a major regulation network during enterovirus infection. We demonstrate that inhibition of mTORC1 activates TFEB, which increases expression of lysosomal and autophagosomal genes, and that TFEB activation facilitates the release of virions in extracellular vesicles via secretory autophagy. Our study provides a rich framework for a system-level understanding of enterovirus-induced perturbations at the protein and signalling pathway levels, forming a base for the development of pharmacological inhibitors to treat enterovirus infections.
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spelling pubmed-74557052020-09-04 Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection Giansanti, Piero Strating, Jeroen R. P. M. Defourny, Kyra A. Y. Cesonyte, Ieva Bottino, Alexia M. S. Post, Harm Viktorova, Ekaterina G. Ho, Vien Quang Tri Langereis, Martijn A. Belov, George A. Nolte-‘t Hoen, Esther N. M. Heck, Albert J. R. van Kuppeveld, Frank J. M. Nat Commun Article The group of enteroviruses contains many important pathogens for humans, including poliovirus, coxsackievirus, rhinovirus, as well as newly emerging global health threats such as EV-A71 and EV-D68. Here, we describe an unbiased, system-wide and time-resolved analysis of the proteome and phosphoproteome of human cells infected with coxsackievirus B3. Of the ~3,200 proteins quantified throughout the time course, a large amount (~25%) shows a significant change, with the majority being downregulated. We find ~85% of the detected phosphosites to be significantly regulated, implying that most changes occur at the post-translational level. Kinase-motif analysis reveals temporal activation patterns of certain protein kinases, with several CDKs/MAPKs immediately active upon the infection, and basophilic kinases, ATM, and ATR engaging later. Through bioinformatics analysis and dedicated experiments, we identify mTORC1 signalling as a major regulation network during enterovirus infection. We demonstrate that inhibition of mTORC1 activates TFEB, which increases expression of lysosomal and autophagosomal genes, and that TFEB activation facilitates the release of virions in extracellular vesicles via secretory autophagy. Our study provides a rich framework for a system-level understanding of enterovirus-induced perturbations at the protein and signalling pathway levels, forming a base for the development of pharmacological inhibitors to treat enterovirus infections. Nature Publishing Group UK 2020-08-28 /pmc/articles/PMC7455705/ /pubmed/32859902 http://dx.doi.org/10.1038/s41467-020-18168-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Giansanti, Piero
Strating, Jeroen R. P. M.
Defourny, Kyra A. Y.
Cesonyte, Ieva
Bottino, Alexia M. S.
Post, Harm
Viktorova, Ekaterina G.
Ho, Vien Quang Tri
Langereis, Martijn A.
Belov, George A.
Nolte-‘t Hoen, Esther N. M.
Heck, Albert J. R.
van Kuppeveld, Frank J. M.
Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
title Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
title_full Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
title_fullStr Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
title_full_unstemmed Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
title_short Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
title_sort dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455705/
https://www.ncbi.nlm.nih.gov/pubmed/32859902
http://dx.doi.org/10.1038/s41467-020-18168-3
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