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Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis.

Publication ,  Journal Article
Heaton, NS; Perera, R; Berger, KL; Khadka, S; Lacount, DJ; Kuhn, RJ; Randall, G
Published in: Proc Natl Acad Sci U S A
October 5, 2010

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 5, 2010

Volume

107

Issue

40

Start / End Page

17345 / 17350

Location

United States

Related Subject Headings

  • Virus Replication
  • Viral Nonstructural Proteins
  • Two-Hybrid System Techniques
  • RNA Interference
  • Humans
  • Fatty Acids
  • Fatty Acid Synthases
  • Dengue Virus
  • Cell Line
  • Animals
 

Citation

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Heaton, N. S., Perera, R., Berger, K. L., Khadka, S., Lacount, D. J., Kuhn, R. J., & Randall, G. (2010). Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci U S A, 107(40), 17345–17350. https://doi.org/10.1073/pnas.1010811107
Heaton, Nicholas S., Rushika Perera, Kristi L. Berger, Sudip Khadka, Douglas J. Lacount, Richard J. Kuhn, and Glenn Randall. “Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis.Proc Natl Acad Sci U S A 107, no. 40 (October 5, 2010): 17345–50. https://doi.org/10.1073/pnas.1010811107.
Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ, Kuhn RJ, et al. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17345–50.
Heaton, Nicholas S., et al. “Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis.Proc Natl Acad Sci U S A, vol. 107, no. 40, Oct. 2010, pp. 17345–50. Pubmed, doi:10.1073/pnas.1010811107.
Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ, Kuhn RJ, Randall G. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17345–17350.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 5, 2010

Volume

107

Issue

40

Start / End Page

17345 / 17350

Location

United States

Related Subject Headings

  • Virus Replication
  • Viral Nonstructural Proteins
  • Two-Hybrid System Techniques
  • RNA Interference
  • Humans
  • Fatty Acids
  • Fatty Acid Synthases
  • Dengue Virus
  • Cell Line
  • Animals