Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
Research Institute for Food and Agriculture, Ryukoku University, Otsu, Japan.
Elife. 2017 Sep 27;6:e26845. doi: 10.7554/eLife.26845.
When activated by the accumulation of unfolded proteins in the endoplasmic reticulum, metazoan IRE1, the most evolutionarily conserved unfolded protein response (UPR) transducer, initiates unconventional splicing of XBP1 mRNA. Unspliced and spliced mRNA are translated to produce pXBP1(U) and pXBP1(S), respectively. pXBP1(S) functions as a potent transcription factor, whereas pXBP1(U) targets pXBP1(S) to degradation. In addition, activated IRE1 transmits two signaling outputs independent of XBP1, namely activation of the JNK pathway, which is initiated by binding of the adaptor TRAF2 to phosphorylated IRE1, and regulated IRE1-dependent decay (RIDD) of various mRNAs in a relatively nonspecific manner. Here, we conducted comprehensive and systematic genetic analyses of the IRE1-XBP1 branch of the UPR using medaka fish and found that the defects observed in XBP1-knockout or IRE1-knockout medaka were fully rescued by constitutive expression of pXBP1(S). Thus, the JNK and RIDD pathways are not required for the normal growth and development of medaka. The unfolded protein response sensor/transducer IRE1-mediated splicing of XBP1 mRNA encoding its active downstream transcription factor to maintain the homeostasis of the endoplasmic reticulum is sufficient for growth and development of medaka fish.
当真核生物 IRE1 被内质网中未折叠蛋白的积累激活时，它会启动 XBP1 mRNA 的非规范剪接。未剪接和剪接的 mRNA 分别被翻译产生 pXBP1(U)和 pXBP1(S)。pXBP1(S)作为一种有效的转录因子发挥作用，而 pXBP1(U)则将 pXBP1(S)靶向降解。此外，激活的 IRE1 独立于 XBP1 传递两种信号输出，即 JNK 途径的激活，该途径是通过衔接蛋白 TRAF2 与磷酸化的 IRE1 结合而启动的，以及以相对非特异性的方式调节各种 mRNA 的 IRE1 依赖性衰减（RIDD）。在这里，我们使用斑马鱼对 UPR 的 IRE1-XBP1 分支进行了全面和系统的遗传分析，发现 XBP1 敲除或 IRE1 敲除斑马鱼中观察到的缺陷可以通过 pXBP1(S)的组成型表达完全挽救。因此，JNK 和 RIDD 途径对于斑马鱼的正常生长和发育不是必需的。未折叠蛋白反应传感器/转导子 IRE1 介导的 XBP1 mRNA 剪接，编码其活性下游转录因子，足以维持内质网的内稳态，这对于斑马鱼的生长和发育是足够的。
