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.

Keywords: endoplasmic reticulum; proteostasis; signalling pathway; stress.

Figure 1

ER molecular machines and contact sites with other organelles. The ER is primarily subdivided into the SER and RER, with the latter characterized by the presence of ribosomes at its cytosolic surface. Alternatively, the ER has been recently classified into the nuclear envelope, ER sheet‐like cisternae and tubular ER (panel 1). The ER forms multiple membrane contact sites with other organelles, including the endosomes and lysosomes (through STARD3, STARD3NL, Mdm1; panel 2), the mitochondria (through Mfn‐2, Sig‐1R, PERK; panel 3), and the PM (through ORAI1, STIM1, Sec22b, VAMP7; panel 4) with various functional implications. The ER plays instrumental roles in secretory and transmembrane protein folding and quality control, protein and lipid trafficking, lipid metabolism, and Ca²⁺ homeostasis, all of these processes being mediated by a diverse series of ER resident proteins (schematically depicted in panels 1 and 5).

Figure 2

Signalling the UPR and downstream pathways. The 3ER stress sensors (PERK, IRE1, ATF6) upon release from BiP, PDIA5, 6 initiate signalling cascades through transcription factor production (ATF4, XBP1s, ATF6f) and associated processes such as RIDD, NFκB activation and ERAD to address the misfolded protein load on the ER. By modulating transcriptional output and translational demand the UPR attempts to re‐establish ER protein folding homeostasis and promote cell survival. If ER stress cannot be resolved then mechanisms are triggered to promote cell death.

Figure 3

UPR disease biomarkers and therapeutic targets. Schematic representation of the UPR signalling pathway as defined in Fig. 2 and annotated with the relevance to disease of each component. The colour code indicates the type of disease (cancer: orange; metabolic disease: red; degenerative disease: blue; infectious disease: green; inflammatory disease: pink) and the lines indicate the role as biomarker (continuous line) or therapeutic target (dashed line).