PMID- 21937645
OWN - NLM
STAT- MEDLINE
DCOM- 20120119
LR  - 20211203
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 85
IP  - 23
DP  - 2011 Dec
TI  - Human cytomegalovirus induces multiple means to combat reactive oxygen species.
PG  - 12585-93
LID - 10.1128/JVI.05572-11 [doi]
AB  - Reactive oxygen species (ROS) are generated as by-products of many cellular 
      processes and can modulate cellular signaling pathways. However, high ROS levels 
      are toxic; thus, intracellular ROS need to be tightly controlled. Therefore, 
      cells use a group of antioxidant molecules and detoxifying enzymes that remove or 
      detoxify reactive species. We found that the level of the antioxidant glutathione 
      is greatly increased in human cytomegalovirus (HCMV)-infected cells due to 
      activation of glutathione synthetic enzymes. In addition, our data suggest that 
      virus-specific mechanisms are used to induce the expression of target antioxidant 
      and detoxifying enzymes critical for the success of the infection. As a result of 
      this virus-induced anti-ROS environment, key signaling kinases, such as the 
      mammalian target of rapamycin (mTOR) kinase in mTOR complex 1 (mTORC1), are 
      protected from inhibition by exogenous hydrogen peroxide (H(2)O(2)). In this 
      regard, we found that phosphorylation of mTOR kinase at serine 2448 (suggested to 
      be activating) was maintained during infection even under ROS stress conditions 
      that inhibited it in uninfected cells. We also show that AMP-dependent kinase 
      (AMPK)-mediated phosphorylation of serine 792 of raptor, the specificity subunit 
      of mTORC1, increases in infected cells after H(2)O(2) treatment. This 
      phosphorylation is normally inhibitory for mTORC1. However, in infected cells 
      this did not result in inhibition of mTORC1 activity, suggesting that inhibitory 
      effects of raptor phosphorylation are circumvented. Overall, our data suggest 
      that HCMV utilizes virus-specific mechanisms to activate a variety of means to 
      protect the cell and mTORC1 from the effects of ROS.
FAU - Tilton, Carisa
AU  - Tilton C
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, School 
      of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6142, USA.
FAU - Clippinger, Amy J
AU  - Clippinger AJ
FAU - Maguire, Tobi
AU  - Maguire T
FAU - Alwine, James C
AU  - Alwine JC
LA  - eng
GR  - F32 AI082893/AI/NIAID NIH HHS/United States
GR  - R01 CA157679/CA/NCI NIH HHS/United States
GR  - R01 CA157846/CA/NCI NIH HHS/United States
GR  - R01 CA157679-01/CA/NCI NIH HHS/United States
GR  - 1F32AI082893/AI/NIAID NIH HHS/United States
GR  - T32 CA115299/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110921
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antioxidants)
RN  - 0 (Oxidants)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Antioxidants/metabolism
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Cytomegalovirus/*pathogenicity
MH  - Cytomegalovirus Infections/*metabolism/pathology/*virology
MH  - Fibroblasts/cytology/metabolism/virology
MH  - Foreskin/cytology/metabolism/virology
MH  - Glutathione/metabolism
MH  - Humans
MH  - Hydrogen Peroxide/pharmacology
MH  - Male
MH  - Oxidants/pharmacology
MH  - Phosphorylation
MH  - RNA, Messenger/genetics
MH  - Reactive Oxygen Species/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
PMC - PMC3209350
EDAT- 2011/09/23 06:00
MHDA- 2012/01/20 06:00
PMCR- 2012/06/01
CRDT- 2011/09/23 06:00
PHST- 2011/09/23 06:00 [entrez]
PHST- 2011/09/23 06:00 [pubmed]
PHST- 2012/01/20 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - JVI.05572-11 [pii]
AID - 5572-11 [pii]
AID - 10.1128/JVI.05572-11 [doi]
PST - ppublish
SO  - J Virol. 2011 Dec;85(23):12585-93. doi: 10.1128/JVI.05572-11. Epub 2011 Sep 21.