Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

Abstract

The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

“…Inositol‐requiring enzyme 1 alpha (IRE1α) is a highly conserved mediator of the UPR . Dissociated GRP78/BiP from IRE1α preferentially binds to unfolded/misfolded proteins, causing dimerization and autophosphorylation of IRE1α through its kinase activity .…”

“…Inositol‐requiring enzyme 1 alpha (IRE1α) is a highly conserved mediator of the UPR . Dissociated GRP78/BiP from IRE1α preferentially binds to unfolded/misfolded proteins, causing dimerization and autophosphorylation of IRE1α through its kinase activity . This leads to an increase in nuclease activity of IRE1α, leading to catalysis of the excision of an unconventional intron of 26 nucleotides in length from the X‐box binding protein 1 (XBP1) mRNA to produce spliced isoform of XBP1 (XBP1s) .…”

“…Moreover, in addition to XBP1 mRNA, IRE1α also cleaves other mRNAs localized in the ER membrane and processes their degradation through a process known as regulated IRE1‐dependent mRNA decay (RIDD) . Emerging evidence suggests that RIDD has a critical role in the maintenance of ER homeostasis by alleviating ER client protein load through mRNA degradation and inhibition of protein synthesis by cleavage of 28S rRNA . (See [,] for more details on the role of IRE1α under ER stress.…”

“…Emerging evidence suggests that RIDD has a critical role in the maintenance of ER homeostasis by alleviating ER client protein load through mRNA degradation and inhibition of protein synthesis by cleavage of 28S rRNA . (See [,] for more details on the role of IRE1α under ER stress. )…”

“…Similar to IRE1α activation, detachment of GRP78/BiP from PERK in the ER luminal domain leads to activation of PERK through its dimerization and auto‐phosphorylation . Activated PERK recruits and phosphorylates a translation initiation factor, eukaryotic translation initiation factor (eIF) 2α, through its kinase activity .…”