Hepatitis C virus non-structural protein NS4B can modulate an unfolded protein response

J Microbiol. 2005 Dec;43(6):529-36.


Viral infection causes stress to the endoplasmic reticulum (ER). The response to endoplasmic reticulum stress, known as the unfolded protein response (UPR), is designed to eliminate misfolded proteins and allow the cell to recover. The role of hepatitis C virus (HCV) non-structural protein NS4B, a component of the HCV replicons that induce UPR, is incompletely understood. We demonstrate that HCV NS4B could induce activating transcription factor (ATF6) and inositol-requiring enzyme 1 (IRE1), to favor the HCV subreplicon and HCV viral replication. HCV NS4B activated the IRE1 pathway, as indicated by splicing of X box-binding protein (Xbp-1) mRNA. However, transcriptional activation of the XBP-1 target gene, EDEM (ER degradation-enhancing alpha-mannosidase-like protein, a protein degradation factor), was inhibited. These results imply that NS4B might induce UPR through ATF6 and IRE1-XBP1 pathways, but might also modify the outcome to benefit HCV or HCV subreplicon replication.

MeSH terms

  • Activating Transcription Factor 6 / metabolism*
  • Blotting, Western
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Endoribonucleases
  • Hepacivirus / physiology*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Splicing
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Regulatory Factor X Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors
  • Viral Nonstructural Proteins / physiology*
  • Virus Replication
  • X-Box Binding Protein 1


  • Activating Transcription Factor 6
  • DNA-Binding Proteins
  • EDEM1 protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Viral Nonstructural Proteins
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • ERN2 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases