Abstract
The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.
Highlights
The endonuclease activity of Inositol-requiring enzyme 1α (IRE1α) allows for its dual function of initiating regulated IRE1-dependent decay (RIDD), as well as activating X-box binding protein-1 (XBP1) by alternative splicing of its mRNA, which promotes the expression of similar protein folding-associated genes
The receptor, along with unfolded proteins are degraded via ER-associated degradation (ERAD), in an effort to reduce the source of endoplasmic reticulum (ER) stress
protein kinase R-like ER kinase (PERK) phosphorylates eukaryotic initiation factor-2α (eIF2α), which orchestrates the reduction in protein synthesis, promoting cytoprotective responses via Activating transcription factor 4 (ATF4)-mediated transcriptional regulation and inducing apoptosis through the activation of C/EBP Homologous Protein (CHOP) in response to chronic ER stress
Summary
Cells are normally in a state of proteostasis, whereby networks of signaling pathways work in concert to maintain the proper synthesis, folding, trafficking, and degradation of proteins. Under pathological or even physiological conditions, as well as in response to chronic stimuli, there is likely to be an accumulation of misfolded or unfolded proteins in the ER. This accumulation is referred to as ER stress and leads to the activation of the unfolded protein response (UPR) that inhibits de novo protein synthesis, while permitting the expression of protein-folding machinery and increasing degradation of unfolded proteins. Autophagy is regulated by complex mechanisms which include pathways affecting cell metabolism, division, and autophagy, including the mevalonate pathway (Miettinen and Bjorklund, 2015). Further consideration of these pathways, is beyond the scope of this review
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