When endoplasmic reticulum (ER) stress occurs, a collection of phylogenetically conserved signaling pathways, termed unfolded protein response (UPR) pathways, monitors the stress level in the ER and is activated to restore homeostasis. If stress is overwhelming, activation of these signaling pathways also leads to apoptosis. The initial response in the ER is fluxed into several parallel branches, i.e., IRE1, PERK, and ATF6 branch. How they coordinate in response to different ER stress levels remains largely unknown. Here, we constructed a dual-reporter system to simultaneously monitor and quantify the response of both the IRE1 and PERK branches. We found that the IRE1 and PERK branches were highly coordinated via mutual inhibition. Furthermore, IRE1 branch was more sensitive to ER stress than the PERK branch under low ER stress and IRE1 activity was attenuated under high ER stress. The differential sensitivity between the two branches arises from the interbranch inhibitor p58IPK, rather than the intra-branch inhibitor GADD34. Our results suggested a model where cells use the antagonistic crosstalk between parallel UPR signaling pathways to fine-tune their activities in response to different ER stress levels.

中文翻译：

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在展开的蛋白质反应过程中，拮抗性串扰微调了IRE1和PERK信号的敏感性

当发生内质网（ER）应激时，系统发育上保守的信号传导途径（称为未折叠蛋白反应（UPR）途径）的集合监视ER中的应激水平并被激活以恢复体内平衡。如果压力不堪重负，这些信号通路的激活也会导致细胞凋亡。ER中的初始响应流入多个并行分支，即IRE1，PERK和ATF6分支。他们如何协调以应对不同的内质网应激水平仍然很大程度上未知。在这里，我们构建了一个双报告器系统，以同时监视和量化IRE1和PERK分支的响应。我们发现IRE1和PERK分支通过相互抑制高度协调。此外，在低ER胁迫下，IRE1分支比PERK分支对ER胁迫更敏感，而在高ER胁迫下IRE1活性减弱。两个分支之间的差异敏感性来自分支间抑制剂p58IPK，而不是分支内抑制剂GADD34。我们的研究结果提出了一个模型，其中细胞利用平行的UPR信号通路之间的拮抗作用来微调它们的活性，以响应不同的ER应激水平。