Science signaling：IRE1α通過促凋亡抵抗促進病毒感染

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2017年6月7日，美國耶魯大學Akiko Iwasaki研究團隊在science signaling發文，發現Xbp1缺陷型細胞對丙型肝炎病毒（HCV）感染引起的抗病毒反應有缺陷，然而，這一過程中細胞I型IFN的生產或應答中未受影響。相反，IRE1α的活化增強，其切割了促細胞凋亡的 miR-125a，導致凋亡減少和病毒複製增加。

未摺疊蛋白反應（UPR）是一種可以檢測和緩解蛋白質摺疊應力的古老的細胞通路。UPR組分X-box結合蛋白1（XBP1）和肌醇依賴酶1α（IRE1α）可以促進I型干擾素（IFN）反應。研究人員發現Xbp1缺陷的小鼠胚胎成纖維細胞和巨噬細胞抗病毒抗性受損。

然而，這不是因為I型IFN應答的缺陷，而是Xbp1缺陷型細胞不能進行病毒誘導的凋亡。而這種在野生型細胞中抑制凋亡的能力也限制了病毒的感染。

研究發現Xbp1缺陷型細胞對凋亡的內源途徑具有抗性。而這一過程涉及核酸酶IRE1α激活的間接機制。

研究觀察到IRE1α依賴的促細胞凋亡的microRNA miR-125a丰度的減少和抗凋亡Bcl-2家族成員的量的相應增加。

XBP1細胞中丙型肝炎病毒（HCV）蛋白NS4B對IRE1α的活化也賦予對凋亡的抵抗，促進病毒複製。此外，與健康對照肝臟相比，研究發現HCV感染患者的肝活檢中IRE1α的活化和miR-125a丰度降低的證據。

這一研究結果揭示了IRE1α在病毒感染細胞中的作用，並提出了非IFN依賴的抗病毒治療的可能靶點。

IRE1α promotes viral infection by conferring resistance to apoptosis

DOI：10.1126/scisignal.aai7814

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 thatXbp1-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 ofXbp1-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.

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