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IRE1? promotes viral infection by conferring resistance to apoptosis.


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 1? (IRE1?) 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 IRE1?. We observed an IRE1?-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 IRE1? 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 IRE1? 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 IRE1? in virally infected cells and suggest a possible target for IFN-independent antiviral therapy.

SUBMITTER: Fink SL 

PROVIDER: S-EPMC5535312 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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IRE1α promotes viral infection by conferring resistance to apoptosis.

Fink Susan L SL   Jayewickreme Teshika R TR   Molony Ryan D RD   Iwawaki Takao T   Landis Charles S CS   Lindenbach Brett D BD   Iwasaki Akiko A  

Science signaling 20170606 482


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 <i>Xbp1</i>-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 <i>Xbp1</i>-deficient cells to underg  ...[more]

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