Document Detail


Human cytomegalovirus induces the activity and expression of acetyl-coenzyme A carboxylase, a fatty acid biosynthetic enzyme whose inhibition attenuates viral replication.
MedLine Citation:
PMID:  21471234     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously reported that human cytomegalovirus (HCMV) infection induces large-scale changes to host cell glycolytic, nucleic acid, and phospholipid metabolism. Here we explore the viral mechanisms involved in fatty acid biosynthetic activation. Our results indicate that HCMV targets ACC1, the rate-limiting enzyme of fatty acid biosynthesis, through multiple mechanisms. HCMV infection was found to activate ACC1 expression, increasing the abundance of both ACC1 mRNA and protein. Viral gene expression but not viral DNA replication was found to be necessary for HCMV-mediated induction of ACC1 levels. HCMV infection was also found to increase the proteolytic processing of SREBP-2, a transcription factor whose proteolytic cleavage is known to activate a variety of phospholipid metabolic genes. Processing of SREBP-2 was found to be dependent on mTOR activity; pharmaceutical inhibition of mTOR blocked HCMV-induced SREBP-2 processing and prevented the induction of fatty acid biosynthesis and ACC1 expression. Independent of the increases in ACC1 expression, HCMV infection also induced ACC1's enzymatic activity. Inhibition of ACC1 through either RNA interference (RNAi) or inhibitor treatment was found to attenuate HCMV replication, and HCMV replication was sensitive to ACC1 inhibition even at the later stages of infection, suggesting a late role for fatty acid biosynthesis during HCMV replication. These findings indicate that HCMV infection actively modulates numerous functional aspects of a key metabolic regulatory enzyme that is important for high-titer viral replication.
Authors:
Cody M Spencer; Xenia L Schafer; Nathaniel J Moorman; Joshua Munger
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-06
Journal Detail:
Title:  Journal of virology     Volume:  85     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-20     Completed Date:  2011-08-04     Revised Date:  2014-04-10    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5814-24     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acetyl-CoA Carboxylase / genetics,  metabolism*
Cell Line
Cytomegalovirus / pathogenicity*
DNA Replication
Fatty Acids / biosynthesis*
Fibroblasts / enzymology,  virology*
Host-Pathogen Interactions*
Humans
RNA, Messenger / genetics,  metabolism*
Sterol Regulatory Element Binding Protein 2 / genetics,  metabolism
Virus Replication
Grant Support
ID/Acronym/Agency:
R01 AI081773/AI/NIAID NIH HHS; R01AI081773/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/RNA, Messenger; 0/SREBF2 protein, human; 0/Sterol Regulatory Element Binding Protein 2; EC 6.4.1.2/Acetyl-CoA Carboxylase
Comments/Corrections

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