The functional role of Ire1 in regulating autophagy and proteasomal degradation under prolonged proteotoxic stress

Abstract

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.

Effect of N-acetyl-l-cysteine on Cell Phenotype and Autophagy in Pichia pastoris Expressing Human Serum Albumin and Porcine Follicle-Stimulating Hormone Fusion Protein

“…Autophagy can be divided into nonselective and selective autophagy, the latter including mitophagy, pexophagy, aggrephagy, ER autophagy, and so on. Environmental factors such as starvation, oxidative stress, or chemical agents can induce autophagy in yeast and mammalian cells [ 43 , 44 , 45 ]. In P. pastoris , pexophagy was induced by transferring cultures on non-fermentative carbon sources (such as methanol or oleate) to glucose.…”