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

Nat Med. 2013 Jun;19(6):722-9. doi: 10.1038/nm.3190. Epub 2013 May 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • 3' Untranslated Regions
  • Active Transport, Cell Nucleus
  • DEAD-box RNA Helicases / physiology
  • Hepatitis C / metabolism*
  • Hepatitis C / virology
  • Humans
  • I-kappa B Kinase / physiology*
  • Lipogenesis*
  • NF-kappa B / physiology
  • Phosphorylation
  • Signal Transduction
  • Sterol Regulatory Element Binding Proteins / physiology
  • Virus Assembly*
  • p300-CBP Transcription Factors / physiology


  • 3' Untranslated Regions
  • NF-kappa B
  • Sterol Regulatory Element Binding Proteins
  • p300-CBP Transcription Factors
  • CHUK protein, human
  • I-kappa B Kinase
  • DDX3X protein, human
  • DEAD-box RNA Helicases

Associated data

  • GEO/GSE46528