Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer's disease

Abstract

Protein folding stress in the endoplasmic reticulum (ER) may lead to activation of the unfolded protein response (UPR), aimed to restore cellular homeostasis via transcriptional and post-transcriptional mechanisms. ER stress is also reported to activate the ER overload response (EOR), which activates transcription via NF-κB. We previously demonstrated that UPR activation is an early event in pre-tangle neurons in Alzheimer's disease (AD) brain. Misfolded and unfolded proteins are degraded via the ubiquitin proteasome system (UPS) or autophagy. UPR activation is found in AD neurons displaying both early UPS pathology and autophagic pathology. Here we investigate whether activation of the UPR and/or EOR is employed to enhance the proteolytic capacity of neuronal cells. Expression of the immunoproteasome subunits β2i and β5i is increased in AD brain. However, expression of the proteasome subunits is not increased by the UPR or EOR. UPR activation does not relocalize the proteasome or increase overall proteasome activity. Therefore proteasomal degradation is not increased by ER stress. In contrast, UPR activation enhances autophagy and LC3 levels are increased in neurons displaying UPR activation in AD brain. Our data suggest that autophagy is the major degradational pathway following UPR activation in neuronal cells and indicate a connection between UPR activation and autophagic pathology in AD brain.

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

“…ER-associated VCP is involved in the UPR, a process that is activated by ER stress leading to the proteasomal degradation of misfolded ER proteins, called ERAD (endoplasmic reticulum-associated degradation) [38]. Interestingly, recent data imply that although UPS-mediated protein degradation is involved, autophagy seems to be the predominant degradation pathway during ER stress and UPR activation [15,16]. We found here that Washc4 deficiency resulted in ER stress in vivo without impairing the proteasomal protein degradation machinery.…”

“…This leads to the cytosolic proteasomal degradation of misfolded proteins, a process called ERAD (endoplasmic reticulum-associated degradation) [14]. Recent evidence suggests that during ER stress and UPR activation macroautophagy is the predominant degradation pathway whereas the UPS seems to play only a minor role [15,16]. …”

Autophagy Promotes Intracellular Degradation of Type I Collagen Induced by Transforming Growth Factor (TGF)-β1

“…The accumulation of unfolded or misfolded proteins caused by mutations in collagen genes, or saturation of protein folding capacity in ER induces ER stress, which is a potent trigger of autophagy (15). A recent study demonstrated that the interruption of correct folding of the pro-Col-I by the depletion of Hsp47 function or misfolded pro-Col-I induced their aggregation in ER, and the aggregates underwent autophagy-mediated degradation (9).…”

“…The process of autophagy involves the formation of double membrane bound vesicles called autophagosomes that envelope and sequester cytoplasmic components, including macromolecular aggregates and cellular organelles for bulk degradation by a lysosomal degradative pathway (11). Autophagy can be up-regulated in response to both external and intracellular factors, including amino acid starvation (12), growth factor withdrawal (13), low cellular energy levels (14), endoplasmic reticulum (ER) stress (15), hypoxia (16), oxidative stress (17), pathogen infection (18), and organelle damage (19). To date, more than 30 genes whose products are involved in autophagy have been identified in yeast, and these have been termed autophagy-related genes (Atg) (20).…”

Role of homocysteinylation of ACE in endothelial dysfunction of arteries

“…In a more wide-ranging consequence of posttranslational modifications of proteins, homocysteinylation of nascent protein can stall or hinder proper folding of proteins and can concomitantly activate the "unfolded protein response" (UPR) within the endoplasmic reticulum (14). Initiation of the UPR can adversely affect emerging proteins in endothelial cells (37), by extending or prolonging required activation of secreted proteins and subsequently evoking Hcy-induced oxidative stress.…”