Document Detail


Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis.
MedLine Citation:
PMID:  20855599     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dengue virus (DENV) modifies cellular membranes to establish its sites of replication. Although the 3D architecture of these structures has recently been described, little is known about the cellular pathways required for their formation and expansion. In this report, we examine the host requirements for DENV replication using a focused RNAi analysis combined with validation studies using pharmacological inhibitors. This approach identified three cellular pathways required for DENV replication: autophagy, actin polymerization, and fatty acid biosynthesis. Further characterization of the viral modulation of fatty acid biosynthesis revealed that a key enzyme in this pathway, fatty acid synthase (FASN), is relocalized to sites of DENV replication. DENV nonstructural protein 3 (NS3) is responsible for FASN recruitment, inasmuch as (i) NS3 expressed in the absence of other viral proteins colocalizes with FASN and (ii) NS3 interacts with FASN in a two-hybrid assay. There is an associated increase in the rate of fatty acid biosynthesis in DENV-infected cells, and de novo synthesized lipids preferentially cofractionate with DENV RNA. Finally, purified recombinant NS3 stimulates the activity of FASN in vitro. Taken together, these experiments suggest that DENV co-opts the fatty acid biosynthetic pathway to establish its replication complexes. This study provides mechanistic insight into DENV membrane remodeling and highlights the potential for the development of therapeutics that inhibit DENV replication by targeting the fatty acid biosynthetic pathway.
Authors:
Nicholas S Heaton; Rushika Perera; Kristi L Berger; Sudip Khadka; Douglas J Lacount; Richard J Kuhn; Glenn Randall
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-20
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-06     Completed Date:  2010-11-16     Revised Date:  2013-04-10    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17345-50     Citation Subset:  IM    
Affiliation:
Department of Microbiology, University of Chicago, Chicago, IL 60637, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Dengue Virus / pathogenicity,  physiology*
Fatty Acid Synthetase Complex / genetics,  metabolism*
Fatty Acids / biosynthesis*
Humans
RNA Interference
Two-Hybrid System Techniques
Viral Nonstructural Proteins / genetics,  metabolism*
Virus Replication / physiology*
Grant Support
ID/Acronym/Agency:
1-U54-AI-057153/AI/NIAID NIH HHS; AI45976/AI/NIAID NIH HHS; R01 GM092829/GM/NIGMS NIH HHS; T32 AI065382-01/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Viral Nonstructural Proteins; EC 6.-/Fatty Acid Synthetase Complex
Comments/Corrections
Comment In:
Nat Rev Microbiol. 2010 Nov;8(11):758   [PMID:  21080554 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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