Endoplasmic reticulum stress in diseases

Abstract

The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.

Keywords: diseases; endoplasmic reticulum stress (ER stress); therapeutic strategies; unfolded protein response (UPR).

FIGURE 1

Unfolded protein signaling pathways. Many factors can cause the accumulation of unfolded and misfolded proteins in the ER to activate ER stress in the cell. The mechanism of the UPR induction is thought to culminate at the point of BiP interaction with the ER‐resident stress sensors IRE1, ATF6, and PERK. Unfolded proteins titrate BiP away from interactions with these sensors, allowing the UPR response to be activated. The activation of these three molecules has the net effect of reducing the load of proteins entering the ER by inhibiting translation and increasing the efflux of nascent proteins by either facilitating their folding through enhanced chaperone production or promoting their degradation, leading to the defense, death, or regulation of the cell.

FIGURE 2

The adaptive UPR. The maladaptive UPR is triggered by persistent activation of the PERK pathway, which occurs due to prolonged and severe ER stress, ultimately resulting in apoptosis (solid red lines). The involvement of IRE1α‐induced JNK and regulated RIDD in ER stress‐induced apoptosis remains uncertain (dashed red lines).

FIGURE 3

An overview of the regulatory mechanism of ER stress in diseases. ER stress plays a crucial role in many diseases, including cardiovascular diseases, neurodegeneration diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. The specific mechanisms by which ER stress contributes to disease include various factors such as genetic mutations, epigenetic modifications, impaired autophagy, oxidative stress, mitochondrial dysfunction, and alterations in metabolism. The figure is created according to the elements in Ref.