MSU-DOE Plant Research Lab, Michigan State University, East Lansing, MI, USA.
Great Lakes Bioenergy Research Center, Michigan State University, East Lansing, MI, USA.
Nat Plants. 2023 Aug;9(8):1333-1346. doi: 10.1038/s41477-023-01480-3. Epub 2023 Aug 10.
Excessive accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, which is an underlying cause of major crop losses and devastating human conditions. ER proteostasis surveillance is mediated by the conserved master regulator of the unfolded protein response (UPR), Inositol Requiring Enzyme 1 (IRE1), which determines cell fate by controlling pro-life and pro-death outcomes through as yet largely unknown mechanisms. Here we report that Arabidopsis IRE1 determines cell fate in ER stress by balancing the ubiquitin-proteasome system (UPS) and UPR through the plant-unique E3 ligase, PHOSPHATASE TYPE 2CA (PP2CA)-INTERACTING RING FINGER PROTEIN 1 (PIR1). Indeed, PIR1 loss leads to suppression of pro-death UPS and the lethal phenotype of an IRE1 loss-of-function mutant in unresolved ER stress in addition to activating pro-survival UPR. Specifically, in ER stress, PIR1 loss stabilizes ABI5, a basic leucine zipper (bZIP) transcription factor, that directly activates expression of the critical UPR regulator gene, bZIP60, triggering transcriptional cascades enhancing pro-survival UPR. Collectively, our results identify new cell fate effectors in plant ER stress by showing that IRE1's coordination of cell death and survival hinges on PIR1, a key pro-death component of the UPS, which controls ABI5, a pro-survival transcriptional activator of bZIP60.
内质网（ER）中错误折叠蛋白质的过度积累会导致 ER 应激，这是主要作物减产和毁灭性人类疾病的根本原因。ER 蛋白稳态监测是由未折叠蛋白反应（UPR）的保守主调控因子肌醇需求酶 1（IRE1）介导的，它通过控制通过迄今为止尚不清楚的机制控制生死结局来决定细胞命运。在这里，我们报告称，拟南芥 IRE1 通过平衡泛素蛋白酶体系统（UPS）和 UPR 来确定 ER 应激中的细胞命运，这是通过植物特有的 E3 连接酶、磷酸酶 2CA（PP2CA）相互作用的环指蛋白 1（PIR1）实现的。事实上，PIR1 的缺失会抑制 UPS 的促死亡作用，以及在未解决的 ER 应激中 IRE1 功能丧失突变体的致死表型，除了激活促存活 UPR 之外。具体而言，在 ER 应激中，PIR1 的缺失稳定了 ABI5，一种碱性亮氨酸拉链（bZIP）转录因子，它直接激活关键 UPR 调节基因 bZIP60 的表达，引发增强促存活 UPR 的转录级联反应。总的来说，我们的研究结果通过表明 IRE1 协调细胞死亡和存活取决于 PIR1，即 UPS 的关键促死亡成分，它控制 ABI5，即 bZIP60 的促存活转录激活剂，从而确定了植物 ER 应激中的新细胞命运效应子。
