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

Abstract

The Unfolded Protein Response (UPR) is an adaptive pathway that restores cellular homeostasis after endoplasmic reticulum (ER) stress. The ER-resident kinase/ribonuclease 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 ER-stress response and characterize its single 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 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.

Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation

“…A possible case in which autophagy is induced independently from mTOR is represented by the unfolded protein response process that is initiated following ER stress [57,58]. Indeed, both IRE1 and PERK, which are the principal mediator of UPR, have been described to induce autophagy independently from mTOR status [39,59]. Our results confirmed [26] that G6PD inhibition caused ER stress and that, if UPR was inhibited by blocking IRE1 or PERK, polydatin was not still able to induce autophagy.…”

The Role of Secretory Pathways in Candida albicans Pathogenesis

“…Post-translational translocation involves the transport of a secreted protein into the ER after the protein has been fully translated. Unlike co-translational translocation, post-translational translocation is independent of SRP and is mediated primarily through cytosolic and ER molecular chaperones [41,[56][57][58]. The process was initially discovered and extensively studied in S. cerevisiae, but specific participants in post-translational translocation have been identified in C. albicans, particularly the heat shock protein 70 (Hsp70p) family, a modified Sec61p complex, and Kar2p [10,59].…”

“…In S. cerevisiae, Ssa proteins are encoded by SSA1-4 genes and demonstrate over 70% homology with C. albicans SSA genes [61,62]. Deletion of S. cerevisiae (Sc) SSA1 results in a growth defect and cytosolic accumulation of preproteins, specifically preproalpha protein [56,57,63,64]. Both SSA1 and SSA2 are expressed on the C. albicans cell wall surface and may play some role in virulence [65].…”

“…Yeast also displays an unfolded protein response (UPR) in response to an accumulation of unfolded or misfolded proteins in the ER lumen. In C. albicans, the UPR is controlled by inositol requiring enzyme Ire1p, a multi-signal transducer [56,[89][90][91]. Under stress conditions, Ire1p initiates the production of the basic-leucine zipper (bZIP) transcriptional factor Hac1p to induce transcription of downstream UPR genes, facilitating both proper protein folding and protein translocation out of the ER into the cytoplasm for degradation [56,89,91].…”

Endoplasmic Reticulum Stress during Mammalian Follicular Atresia

“…However, in Arabidopsis thaliana, RNase activity of IRE1β, but not its protein kinase activity, is required for ER stress-mediated autophagy [73]. In Dictyostelium, the response to ER stress involves the combined activation of an IRE1α-dependent gene expression program and the autophagy pathway [74]. In mammalian cells, the spliced form of XBP 1 upregulates Nedd4-2, an E3 ubiquitin ligase involved in targeting proteins for subsequent degradation, in response to ER stress.…”