A bimodal switch in global protein translation coupled to eIF4H relocalisation during advancing cell-cell transmission of herpes simplex virus

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Title: A bimodal switch in global protein translation coupled to eIF4H relocalisation during advancing cell-cell transmission of herpes simplex virus
Authors: Teo, CSH
O'Hare, P
Item Type: Journal Article
Abstract: We used the bioorthogonal protein precursor, homopropargylglycine (HPG) and chemical ligation to fluorescent capture agents, to define spatiotemporal regulation of global translation during herpes simplex virus (HSV) cell-to-cell spread at single cell resolution. Translational activity was spatially stratified during advancing infection, with distal uninfected cells showing normal levels of translation, surrounding zones at the earliest stages of infection with profound global shutoff. These cells further surround previously infected cells with restored translation close to levels in uninfected cells, reflecting a very early biphasic switch in translational control. While this process was dependent on the virion host shutoff (vhs) function, in certain cell types we also observed temporally altered efficiency of shutoff whereby during early transmission, naïve cells initially exhibited resistance to shutoff but as infection advanced, naïve target cells succumbed to more extensive translational suppression. This may reflect spatiotemporal variation in the balance of oscillating suppression-recovery phases. Our results also strongly indicate that a single particle of HSV-2, can promote pronounced global shutoff. We also demonstrate that the vhs interacting factor, eIF4H, an RNA helicase accessory factor, switches from cytoplasmic to nuclear localisation precisely correlating with the initial shutdown of translation. However translational recovery occurs despite sustained eIF4H nuclear accumulation, indicating a qualitative change in the translational apparatus before and after suppression. Modelling simulations of high multiplicity infection reveal limitations in assessing translational activity due to sampling frequency in population studies and how analysis at the single cell level overcomes such limitations. The work reveals new insight and a revised model of translational manipulation during advancing infection which has important implications both mechanistically and with regards to the physiological role of translational control during virus propagation. The work also demonstrates the potential of bioorthogonal chemistry for single cell analysis of cellular metabolic processes during advancing infections in other virus systems.
Issue Date: 20-Jul-2018
Date of Acceptance: 2-Jul-2018
URI: http://hdl.handle.net/10044/1/62009
DOI: https://dx.doi.org/10.1371/journal.ppat.1007196
ISSN: 1553-7366
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS Pathogens
Volume: 14
Issue: 7
Copyright Statement: © 2018 Teo, O’Hare. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
VIRION-HOST-SHUTOFF
NEWLY SYNTHESIZED PROTEINS
STRESS GRANULE FORMATION
MESSENGER-RNA DECAY
VHS PROTEIN
GENE UL41
QUANTITATIVE PROTEOMICS
MAMMALIAN-CELLS
CLICK CHEMISTRY
HSV INFECTIONS
Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
VIRION-HOST-SHUTOFF
NEWLY SYNTHESIZED PROTEINS
STRESS GRANULE FORMATION
MESSENGER-RNA DECAY
VHS PROTEIN
GENE UL41
QUANTITATIVE PROTEOMICS
MAMMALIAN-CELLS
CLICK CHEMISTRY
HSV INFECTIONS
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Virology
Publication Status: Published
Article Number: e1007196
Online Publication Date: 2018-07-20
Appears in Collections:Department of Medicine
Faculty of Medicine



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