IRE1α promotes viral infection by conferring resistance to apoptosis

Sci Signal. 2017 Jun 6;10(482):eaai7814. doi: 10.1126/scisignal.aai7814.

Abstract

The unfolded protein response (UPR) is an ancient cellular pathway that detects and alleviates protein-folding stresses. The UPR components X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1α (IRE1α) promote type I interferon (IFN) responses. We found that Xbp1-deficient mouse embryonic fibroblasts and macrophages had impaired antiviral resistance. However, this was not because of a defect in type I IFN responses but rather an inability of Xbp1-deficient cells to undergo viral-induced apoptosis. The ability to undergo apoptosis limited infection in wild-type cells. Xbp1-deficient cells were generally resistant to the intrinsic pathway of apoptosis through an indirect mechanism involving activation of the nuclease IRE1α. We observed an IRE1α-dependent reduction in the abundance of the proapoptotic microRNA miR-125a and a corresponding increase in the amounts of the members of the antiapoptotic Bcl-2 family. The activation of IRE1α by the hepatitis C virus (HCV) protein NS4B in XBP1-proficient cells also conferred apoptosis resistance and promoted viral replication. Furthermore, we found evidence of IRE1α activation and decreased miR-125a abundance in liver biopsies from patients infected with HCV compared to those in the livers of healthy controls. Our results reveal a prosurvival role for IRE1α in virally infected cells and suggest a possible target for IFN-independent antiviral therapy.

MeSH terms

  • Animals
  • Apoptosis*
  • Case-Control Studies
  • Cells, Cultured
  • Endoribonucleases / metabolism*
  • Female
  • Hepacivirus / pathogenicity
  • Hepatitis C / metabolism
  • Hepatitis C / pathology
  • Hepatitis C / virology*
  • Herpes Simplex / metabolism
  • Herpes Simplex / pathology
  • Herpes Simplex / virology*
  • Humans
  • Liver / virology
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Protein Serine-Threonine Kinases / metabolism*
  • Simplexvirus / pathogenicity
  • Vesicular Stomatitis / metabolism
  • Vesicular Stomatitis / pathology
  • Vesicular Stomatitis / virology*
  • Vesicular stomatitis Indiana virus / pathogenicity
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication
  • X-Box Binding Protein 1 / physiology

Substances

  • MIRN125 microRNA, human
  • MicroRNAs
  • NS4B protein, flavivirus
  • Viral Nonstructural Proteins
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases