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

Autor:	Giansanti P; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.; Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, The Netherlands.; Technical University, Munich, Germany., Strating JRPM; Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands.; Viroclinics Biosciences, Rotterdam, The Netherlands., Defourny KAY; Division of Cell Biology, Metabolism & Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM, Utrecht, The Netherlands., Cesonyte I; Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands., Bottino AMS; Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands., Post H; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.; Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, The Netherlands., Viktorova EG; Department of Veterinary Medicine, University of Maryland and VA-MD College of Veterinary Medicine, College Park, MD, 20742, USA., Ho VQT; Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands.; Amsterdam University Medical Center, Amsterdam, The Netherlands., Langereis MA; Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands.; MSD Animal Health, Boxmeer, The Netherlands., Belov GA; Department of Veterinary Medicine, University of Maryland and VA-MD College of Veterinary Medicine, College Park, MD, 20742, USA., Nolte-'t Hoen ENM; Division of Cell Biology, Metabolism & Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM, Utrecht, The Netherlands., Heck AJR; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. a.j.r.heck@uu.nl.; Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, The Netherlands. a.j.r.heck@uu.nl., van Kuppeveld FJM; Virology Section, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL, Utrecht, The Netherlands. f.j.m.vankuppeveld@uu.nl.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Aug 28; Vol. 11 (1), pp. 4332. Date of Electronic Publication: 2020 Aug 28.
DOI:	10.1038/s41467-020-18168-3
Abstrakt:	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.
Databáze:	MEDLINE
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