PMID- 24920814
OWN - NLM
STAT- MEDLINE
DCOM- 20141212
LR  - 20211021
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 88
IP  - 17
DP  - 2014 Sep 1
TI  - The herpes simplex virus 1 virion host shutoff protein enhances translation of 
      viral late mRNAs by preventing mRNA overload.
PG  - 9624-32
LID - 10.1128/JVI.01350-14 [doi]
AB  - We recently demonstrated that the virion host shutoff (vhs) protein, an 
      mRNA-specific endonuclease, is required for efficient herpes simplex virus 1 
      (HSV-1) replication and translation of viral true-late mRNAs, but not other viral 
      and cellular mRNAs, in many cell types (B. Dauber, J. Pelletier, and J. R. 
      Smiley, J. Virol. 85:5363-5373, 2011, http://dx.doi.org/10.1128/JVI.00115-11). 
      Here, we evaluated whether the structure of true-late mRNAs or the timing of 
      their transcription is responsible for the poor translation efficiency in the 
      absence of vhs. To test whether the highly structured 5' untranslated region 
      (5'UTR) of the true-late gC mRNA is the primary obstacle for translation 
      initiation, we replaced it with the less structured 5'UTR of the gamma-actin mRNA. 
      However, this mutation did not restore translation in the context of a 
      vhs-deficient virus. We then examined whether the timing of transcription affects 
      translation efficiency at late times. To this end, we engineered a vhs-deficient 
      virus mutant that transcribes the true-late gene US11 with immediate-early 
      kinetics (IEUS11-DeltaSma). Interestingly, IEUS11-DeltaSma showed increased translational 
      activity on the US11 transcript at late times postinfection, and US11 protein 
      levels were restored to wild-type levels. These results suggest that mRNAs can 
      maintain translational activity throughout the late stage of infection if they 
      are present before translation factors and/or ribosomes become limiting. Taken 
      together, these results provide evidence that in the absence of the 
      mRNA-destabilizing function of vhs, accumulation of viral mRNAs overwhelms the 
      capacity of the host translational machinery, leading to functional exclusion of 
      the last mRNAs that are made during infection. IMPORTANCE: The process of mRNA 
      translation accounts for a significant portion of a cell's energy consumption. To 
      ensure efficient use of cellular resources, transcription, translation, and mRNA 
      decay are tightly linked and highly regulated. However, during virus infection, 
      the overall amount of mRNA may increase drastically, possibly overloading the 
      capacity of the translation apparatus. Our results suggest that the HSV-1 vhs 
      protein, an mRNA-specific endoribonuclease, prevents mRNA overload during 
      infection, thereby allowing translation of late viral mRNAs. The requirement for 
      vhs varies between cell types. Further studies of the basis for this difference 
      likely will offer insights into how cells regulate overall mRNA levels and access 
      to the translational apparatus.
CI  - Copyright (c) 2014, American Society for Microbiology. All Rights Reserved.
FAU - Dauber, Bianca
AU  - Dauber B
AD  - Li Ka Shing Institute of Virology, Department of Medical Microbiology and 
      Immunology, University of Alberta, Edmonton, Alberta, Canada.
FAU - Saffran, Holly A
AU  - Saffran HA
AD  - Li Ka Shing Institute of Virology, Department of Medical Microbiology and 
      Immunology, University of Alberta, Edmonton, Alberta, Canada.
FAU - Smiley, James R
AU  - Smiley JR
AD  - Li Ka Shing Institute of Virology, Department of Medical Microbiology and 
      Immunology, University of Alberta, Edmonton, Alberta, Canada 
      jim.smiley@ualberta.ca.
LA  - eng
GR  - MOP 37995/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140611
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Viral)
RN  - 0 (Viral Proteins)
RN  - 118367-50-3 (virion host shutoff protein, Simplexvirus)
RN  - EC 3.1.- (Ribonucleases)
SB  - IM
MH  - Animals
MH  - Chlorocebus aethiops
MH  - HeLa Cells
MH  - Herpesvirus 1, Human/genetics/*physiology
MH  - Humans
MH  - *Protein Biosynthesis
MH  - RNA, Messenger/*metabolism
MH  - RNA, Viral/*metabolism
MH  - Ribonucleases/*metabolism
MH  - Vero Cells
MH  - Viral Proteins/*biosynthesis/metabolism
PMC - PMC4136367
EDAT- 2014/06/13 06:00
MHDA- 2014/12/17 06:00
PMCR- 2015/03/01
CRDT- 2014/06/13 06:00
PHST- 2014/06/13 06:00 [entrez]
PHST- 2014/06/13 06:00 [pubmed]
PHST- 2014/12/17 06:00 [medline]
PHST- 2015/03/01 00:00 [pmc-release]
AID - JVI.01350-14 [pii]
AID - 01350-14 [pii]
AID - 10.1128/JVI.01350-14 [doi]
PST - ppublish
SO  - J Virol. 2014 Sep 1;88(17):9624-32. doi: 10.1128/JVI.01350-14. Epub 2014 Jun 11.