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Multiple post-transcriptional strategies to regulate the herpes simplex virus type 1 vhs endoribonuclease

Elliott, Gillian, Pheasant, Kathleen, Ebert-Keel, Katja, Stylianou, Julianna, Franklyn, Ashley and Jones, Juliet (2018) Multiple post-transcriptional strategies to regulate the herpes simplex virus type 1 vhs endoribonuclease Journal of Virology.

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Abstract

The HSV1 virion host shutoff (vhs) protein is an endoribonuclease that binds to the cellular translation initiation machinery and degrades associated mRNAs, resulting in shut-off of host protein synthesis. Hence its unrestrained activity is considered to be lethal, and it has been proposed that vhs is regulated by two other virus proteins, VP22 and VP16. We have found that during infection, translation of vhs requires VP22 but not the VP22-VP16 complex. Moreover, in the absence of VP22, vhs is not overactive against cellular or viral transcripts. In transfected cells, vhs was also poorly translated, correlating with aberrant localization of its mRNA. Counterintuitively, vhs mRNA was predominantly nuclear in cells where vhs protein was detected. Likewise, transcripts from co-transfected plasmids were also retained in the same nuclei where vhs mRNA was located, while polyA binding protein (PABP) was relocalised to the nucleus in a vhs-dependent manner, implying a general block to mRNA export. Co-expression of VP16 and VP22 rescued cytoplasmic localization of vhs mRNA but failed to rescue vhs translation. We identified a 230-nucleotide sequence in the 5’ region of vhs that blocked its translation and, when transferred to a heterologous GFP transcript, reduced translation without altering mRNA levels or localization. We propose that expression of vhs is tightly regulated by a combination of inherent untranslatability and auto-induced nuclear retention of its mRNA that results in a negative feedback loop, with nuclear retention but not translation of vhs mRNA being the target of rescue by the vhs-VP16-VP22 complex.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Elliott, Gilliang.elliott@surrey.ac.uk
Pheasant, Kathleenk.pheasant@surrey.ac.uk
Ebert-Keel, Katjak.ebert-keel@surrey.ac.uk
Stylianou, Julianna
Franklyn, Ashley
Jones, Julietj.l.jones@surrey.ac.uk
Date : 2018
DOI : 10.1128/JVI.00818-18
Copyright Disclaimer : Copyright © 2018 Elliott et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Related URLs :
Depositing User : Clive Harris
Date Deposited : 13 Jun 2018 07:13
Last Modified : 07 Nov 2018 08:43
URI: http://epubs.surrey.ac.uk/id/eprint/847042

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