IRE1α promotes viral infection by conferring resistance to apoptosis

  • Sci Signal. 2017 Jun 6;10(482):eaai7814. doi: 10.1126/scisignal.aai7814.
Susan L Fink  1  2  3 ,  Teshika R Jayewickreme  4 ,  Ryan D Molony  4 ,  Takao Iwawaki  5 ,  Charles S Landis  6 ,  Brett D Lindenbach  7  8 ,  Akiko Iwasaki  1  9
Affiliations
  • 1. Department of Immunobiology, Yale University, New Haven, CT 06520, USA. [email protected] [email protected].
  • 2. Department of Laboratory Medicine, Yale University, New Haven, CT 06520, USA.
  • 3. Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
  • 4. Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
  • 5. Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
  • 6. Division of Gastroenterology and Hepatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • 7. Department of Microbial Pathogenesis, Yale University, New Haven, CT 06520, USA.
  • 8. Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA.
  • 9. Howard Hughes Medical Institute, Chevy Chase, MD 20814, USA.
PMID: 28588082 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.