4.5 Article

IRE1α promotes viral infection by conferring resistance to apoptosis

期刊

SCIENCE SIGNALING
卷 10, 期 482, 页码 -

出版社

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aai7814

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资金

  1. Howard Hughes Medical Institute
  2. NIH [T32 HL007974]
  3. [NIH R01 AI054359]
  4. [AI064705]
  5. [K08 AI119142]
  6. [R01 AI087925]

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

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