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Abstract
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.
Here, Giansanti et al. perform a system-wide and time-resolved characterization of the changes in the host cell proteome and phosphoproteome of cells infected with the enterovirus coxsackievirus B3 during a full round of replication and identify mTORC1 signalling as a major regulation network during virus infection.
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1 Utrecht University, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); Netherlands Proteomics Centre, Utrecht, The Netherlands (GRID:grid.4818.5) (ISNI:0000 0001 0791 5666); Technical University, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966)
2 Utrecht University, Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); Viroclinics Biosciences, Rotterdam, The Netherlands (GRID:grid.5477.1)
3 Utrecht University, Division of Cell Biology, Metabolism & Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234)
4 Utrecht University, Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234)
5 Utrecht University, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); Netherlands Proteomics Centre, Utrecht, The Netherlands (GRID:grid.4818.5) (ISNI:0000 0001 0791 5666)
6 University of Maryland and VA-MD College of Veterinary Medicine, Department of Veterinary Medicine, College Park, USA (GRID:grid.164295.d) (ISNI:0000 0001 0941 7177)
7 Utrecht University, Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); Amsterdam University Medical Center, Amsterdam, The Netherlands (GRID:grid.5477.1)
8 Utrecht University, Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); MSD Animal Health, Boxmeer, The Netherlands (GRID:grid.5477.1)