Research ArticleImmunology

IRE1α promotes viral infection by conferring resistance to apoptosis

See allHide authors and affiliations

Sci. Signal.  06 Jun 2017:
Vol. 10, Issue 482, eaai7814
DOI: 10.1126/scisignal.aai7814

You are currently viewing the abstract.

View Full Text

Resisting death by virus

The unfolded protein response (UPR) alleviates the cellular stress caused by the accumulation of proteins, such as that occurring during viral infection. During the UPR, processing of Xbp1 mRNA by the nuclease IRE1α generates the transcription factor XBP1, which drives the expression of genes encoding type I interferons (IFNs). Fink et al. found that Xbp1-deficient cells had defective antiviral responses to infection by hepatitis C virus (HCV); however, the cells were not compromised in type I IFN production or responses. Instead, these cells showed increased activation of IRE1α, which cleaved the proapoptotic microRNA miR-125a, leading to decreased apoptosis and increased viral replication. Liver biopsies from HCV-infected patients also showed increased IRE1α activation and decreased miR-125a abundance. Together, these data suggest that IRE1α functions to enhance cell survival in response to viral infection and may provide a potential therapeutic target.


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.

View Full Text