Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection.
Animals
Autophagy
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/ genetics
Cell Line
Cell Survival
Coxsackievirus Infections
/ metabolism
Enterovirus
/ physiology
Enterovirus B, Human
/ physiology
Gene Knockout Techniques
HeLa Cells
Host-Pathogen Interactions
/ physiology
Humans
Mechanistic Target of Rapamycin Complex 1
Phosphorylation
Proteome
/ analysis
Signal Transduction
Viral Proteins
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 08 2020
28 08 2020
Historique:
received:
22
07
2019
accepted:
06
08
2020
entrez:
30
8
2020
pubmed:
30
8
2020
medline:
18
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32859902
doi: 10.1038/s41467-020-18168-3
pii: 10.1038/s41467-020-18168-3
pmc: PMC7455705
doi:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
Proteome
0
TFEB protein, human
0
Viral Proteins
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4332Subventions
Organisme : NIAID NIH HHS
ID : R01 AI125561
Pays : United States
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