IreA Controls Endoplasmic Reticulum Stress-Induced Autophagy and Survival through Homeostasis Recovery

The unfolded protein response (UPR) is an adaptive pathway that restores cellular homeostasis after endoplasmic reticulum (ER) stress. The ER-resident kinase/RNase Ire1 is the only UPR sensor conserved during evolution. Autophagy, a lysosomal degradative pathway, also contributes to the recovery of cell homeostasis after ER stress, but the interplay between these two pathways is still poorly understood. We describe the Dictyostelium discoideum ER stress response and characterize its single bona fide Ire1 orthologue, IreA. We found that tunicamycin (TN) triggers a gene-expression reprogramming that increases the protein folding capacity of the ER and alleviates ER protein load. Further, IreA is required for cell survival after TN-induced ER stress and is responsible for nearly 40% of the transcriptional changes induced by TN. The response of Dictyostelium cells to ER stress involves the combined activation of an IreA-dependent gene expression program and the autophagy pathway. These two pathways are independently activated in response to ER stress but, interestingly, autophagy requires IreA at a later stage for proper autophagosome formation. We propose that unresolved ER stress in cells lacking IreA causes structural alterations of the ER, leading to a late-stage blockade of autophagy clearance. This unexpected functional link may critically affect eukaryotic cell survival under ER stress.