Department of Biotechnology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, India.
FEBS J. 2023 Jun;290(12):3270-3289. doi: 10.1111/febs.16747. Epub 2023 Feb 23.
Inhibition of endoribonuclease/kinase Ire1 has shown beneficial effects in many proteotoxicity-induced pathology models. The mechanism by which this occurs has not been elucidated completely. Using a proteotoxic yeast model of Huntington's disease, we show that the deletion of Ire1 led to lower protein aggregation at longer time points. The rate of protein degradation was higher in ΔIre1 cells. We monitored the two major protein degradation mechanisms in the cell. The increase in expression of Rpn4, coding for the transcription factor controlling proteasome biogenesis, was higher in ΔIre1 cells. The chymotrypsin-like proteasomal activity was also significantly enhanced in these cells at later time points of aggregation. The gene and protein expression levels of the autophagy gene Atg8 were higher in ΔIre1 than in wild-type cells. Significant increase in autophagy flux was also seen in ΔIre1 cells at later time points of aggregation. The results suggest that the deletion of Ire1 activates UPR-independent arms of the proteostasis network, especially under conditions of aggravated stress. Thus, the inhibition of Ire1 may regulate UPR-independent cellular stress-response pathways under prolonged stress.
内质核酸内切酶/激酶 Ire1 的抑制作用已在许多蛋白毒性诱导的病理学模型中显示出有益效果。但这一作用发生的机制尚未完全阐明。我们使用亨廷顿病的蛋白毒性酵母模型表明，Ire1 的缺失导致在更长的时间点蛋白质聚集减少。ΔIre1 细胞中的蛋白质降解速度更高。我们监测了细胞中的两种主要蛋白质降解机制。控制蛋白酶体生物发生的转录因子编码基因 Rpn4 的表达在ΔIre1 细胞中增加。在聚集的后期，这些细胞中的糜蛋白酶样蛋白酶体活性也显著增强。ΔIre1 细胞中自噬基因 Atg8 的基因和蛋白表达水平高于野生型细胞。在聚集的后期，ΔIre1 细胞中的自噬通量也显著增加。结果表明，Ire1 的缺失激活了未折叠蛋白反应（UPR）独立的蛋白稳态网络分支，尤其是在应激加重的情况下。因此，Ire1 的抑制作用可能在长时间应激下调节 UPR 独立的细胞应激反应途径。
