Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly

Qisheng Li, Véronique Pène, Siddharth Krishnamurthy, Helen Cha, T. Jake Liang

Research output: Contribution to journalArticle

Abstract

Hepatitis C virus (HCV) interacts extensively with host factors to not only establish productive infection but also trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IκB kinase-α (IKK-α) is a crucial host factor for HCV. Here we describe a new nuclear factor κB (NF-κB)-independent and kinase-mediated nuclear function of IKK-α in HCV assembly. HCV, through its 3' untranslated region, interacts with DEAD box polypeptide 3, X-linked (DDX3X) to activate IKK-α, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving sterol regulatory element-binding proteins (SREBPs). This innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKK-α suppress HCV infection and IKK-α-induced lipogenesis, offering a proof-of-concept approach for new HCV therapeutic development. Our results show that HCV uses a novel mechanism to exploit intrinsic innate responses and hijack lipid metabolism, which may contribute to high chronicity rates and the pathological hallmark of steatosis in HCV infection.

Original languageEnglish (US)
Pages (from-to)722-729
Number of pages8
JournalNature Medicine
Volume19
Issue number6
DOIs
StatePublished - Jun 2013
Externally publishedYes

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Virus Assembly
Lipogenesis
Virus Diseases
Viruses
Hepacivirus
Phosphotransferases
Genes
Sterol Regulatory Element Binding Proteins
3' Untranslated Regions
Pathologic Processes
Lipid Metabolism
Small Interfering RNA
Genome
Lipids
Peptides

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly. / Li, Qisheng; Pène, Véronique; Krishnamurthy, Siddharth; Cha, Helen; Liang, T. Jake.

In: Nature Medicine, Vol. 19, No. 6, 06.2013, p. 722-729.

Research output: Contribution to journalArticle

Li, Qisheng ; Pène, Véronique ; Krishnamurthy, Siddharth ; Cha, Helen ; Liang, T. Jake. / Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly. In: Nature Medicine. 2013 ; Vol. 19, No. 6. pp. 722-729.
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