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

IRE1α promotes viral infection by conferring resistance to apoptosis.

Author information

1
Department of Immunobiology, Yale University, New Haven, CT 06520, USA. akiko.iwasaki@yale.edu sfink@uw.edu.
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.

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.

PMID:
28588082
PMCID:
PMC5535312
DOI:
10.1126/scisignal.aai7814
[Indexed for MEDLINE]
Free PMC Article

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