IRE1α promotes viral infection by conferring resistance to apoptosis.

Autor:	Fink SL; Department of Immunobiology, Yale University, New Haven, CT 06520, USA. akiko.iwasaki@yale.edu sfink@uw.edu.; Department of Laboratory Medicine, Yale University, New Haven, CT 06520, USA.; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA., Jayewickreme TR; Department of Immunobiology, Yale University, New Haven, CT 06520, USA., Molony RD; Department of Immunobiology, Yale University, New Haven, CT 06520, USA., Iwawaki T; Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan., Landis CS; Division of Gastroenterology and Hepatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA., Lindenbach BD; Department of Microbial Pathogenesis, Yale University, New Haven, CT 06520, USA.; Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA., Iwasaki A; Department of Immunobiology, Yale University, New Haven, CT 06520, USA. akiko.iwasaki@yale.edu sfink@uw.edu.; Howard Hughes Medical Institute, Chevy Chase, MD 20814, USA.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2017 Jun 06; Vol. 10 (482). Date of Electronic Publication: 2017 Jun 06.
DOI:	10.1126/scisignal.aai7814
Abstrakt:	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. (Copyright © 2017, American Association for the Advancement of Science.)
Databáze:	MEDLINE
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