Endoplasmic reticulum stress (ERS) refers to a physiological and pathological process of endoplasmic reticulum homeostasis imbalance and functional disorder. A variety of factors, such as sugar deprivation, oxidative stress, ischemia and hypoxia, virus infection or calcium ion imbalance, etc., cause endoplasmic reticulum stress.
Cells respond to endoplasmic reticulum stress by initiating a defense process called the unfolded protein response (UPR). UPR is composed of eukaryotic cellular mechanisms designed to adapt and protect the cell's survival. UPR is a process of self-compensation and self-protection by the body, which aims to eliminate misfolded proteins within the endoplasmic reticulum and restore endoplasmic reticulum homeostasis. If the disorder in endoplasmic reticulum exceeds the cell's regulatory ability, it will break endoplasmic reticulum balance, which starts the apoptosis process dependent on caspase12, inducing apoptosis or death, thereby eliminating defective cells.
During the period of endoplasmic reticulum stress, the body up-regulates endoplasmic reticulum chaperone protein, inhibits certain proteins translation and initiates endoplasmic reticulum related protein degradation. And the body also increases the expression of emergency protein genes to improve the physiological state of cells and strengthen the self-repair function of the endoplasmic reticulum. Endoplasmic reticulum stress is a self-protective function of cells.
On the contrary, long-term and severe endoplasmic reticulum stress can impair cell function and even cause apoptosis. Besides, the endoplasmic reticulum stress pathway is also involved in the occurrence of many diseases.
Endoplasmic reticulum stress mainly includes three signaling pathways: unfolded protein response, endoplasmic reticulum overload response, and sterol cascade reaction. Here, we mainly introduce the well-studied unfolding protein response signaling pathway. Its ultimate goal is to help protein correctly fold by reducing protein synthesis, promoting protein degradation and increasing molecular chaperone synthesis.
In the stress state of eukaryotic endoplasmic reticulum, unfolded or misfolded proteins accumulate in the endoplasmic reticulum lumen, triggering the UPR. UPR is an important marker of ER stress. In the non-stress state of endoplasmic reticulum, BiP binds to PERK (double-stranded RNA-dependent protein kinase (PKR)-like ER kinase), IRE1 (inositol requiring enzyme 1) and ATF6 (activating transcription factor 6), thus inhibiting the UPR signaling.
Once unfolded or misfolded proteins are too more to be dealt with by the chaperone proteins residing in the endoplasmic reticulum, the endoplasmic reticulum stress response begins. Subsequently, the expression of GPR78 in the endoplasmic reticulum lumen significantly increases. And then, the chaperone molecule GRP78/BiP is released and binds to unfoldable or misfolded proteins, activating PERK, IRE1, and ATF6.
There are two isomers of IRE1: IRE1 alpha and IRE1 beta. In the endoplasmic reticulum stress state, IRE1 alpha phosphorylates itself and then activates its endonuclease activity. Activated IRE1 alpha splices transcription factors X box-binding protein 1 (XBP1) mRNA (no translation activity) and gets active splicing XBP1s. Splicing XBP1s promotes the expression of UPR target molecules containing ERSE (endoplasmic reticulum stress-responsive element) such as GRP78/BiP, which enhances their ability to correctly fold protein in the endoplasmic reticulum. Moreover, misfolded proteins at the ends bind to BiP and then are degraded by the proteasome, a process known as endoplasmic reticulum-associated degradation (ERAD).
ATF6 dissociates from GRP78/BiP and transfers to Golgi. ATF6 is activated after being cut by Golgi membrane protease site 1 protease (S1P) and site 2 proteases (S2P). Next, functional fragments containing basic leucine zipping structure are released and enter the nucleus to activate the transcription of endoplasmic reticulum stress gene.
PERK has Serine/Threonine kinase activity. When endoplasmic reticulum is stressed, PERK separates from the molecular chaperone GRP78 and then is activated. PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2 alpha) and inactivates it, thereby inhibiting protein translation and synthesis, but activating ATF4 expression, which leads to the up-regulation of CHOP expression. CHOP is an ERS-associated apoptotic molecule that facilitates apoptosis or death. This regulation of translation level can effectively reduce the nascent proteins in the endoplasmic reticulum, diminish the load of the endoplasmic reticulum, decreasing the unfolded and misfolded proteins.
Under unsolvable endoplasmic reticulum stress, UPR is hyperactivated, inducing cellular dysfunction and death. The study of the accumulation of misfolded proteins in the brains of patients with Alzheimer's disease (AD) suggests that changes in endoplasmic reticulum homeostasis may be associated with neurodegenerative events in this disease.
Endoplasmic reticulum stress is an important marker of chronic metabolic disease. As anabolism active cells, the cells of the metabolic system have highly developed endoplasmic reticulum. The endoplasmic reticulum is regarded as a "metabolic sensor", which has a wide and close relationship with the endocrine network. Stress in the endoplasmic reticulum is a key factor to trigger metabolic diseases. Studies have found that endoplasmic reticulum stress induces the formation of insulin resistance in the liver, muscle ＆ adipose tissue, and promotes the development of type II diabetes by affecting two pathways mediating insulin signaling. And type II diabetic mice treated with the chemical chaperone were observed to restore insulin sensitivity.
Parkinson's disease (PD) is a degenerative disease of the central nervous system. It is common in middle-aged and elderly people. Its main pathological feature is the accumulation of misfolded alpha-synuclein in the brain. Endoplasmic reticulum stress has been found in rabbit, mouse and rat models of Parkinson's disease.
As a possible common pathway of various stress processes, endoplasmic reticulum stress involves in the occurrence and development of a variety of inflammatory diseases by coupling with intracellular inflammatory response signal transduction pathway through the UPR pathway. Having a better understanding of the relationship between endoplasmic reticulum stress and inflammation will help us better understand the pathological mechanism of related inflammatory diseases and develop new therapeutic approaches for these diseases.