Table 1.
ER stress and associated diseases.
| Diseases and conditions | Proteins involved | Mechanism | References |
|---|---|---|---|
| Alzheimer’s disease (AD) | GRP78, CHOP/GADD153, PERK, eIF2α, and IRE1α | ER stress proteins such as GRP78 and phosphorylated forms of PERK, eIF2α, and IRE1α in AD are studied. During prolonged ER stress in AD brains, proapoptotic components such as ATF4-CHOP are highly increased. Evidence suggests that the expression of not only GRP78 but also of PDI, target genes of XBP1, is increased in AD. XBP1 is increased in AD and caspase-3, 4, and 12 are also increased in AD. However, the UPR apoptotic pathway was not activated in a transgenic aged mouse model of AD (Tg2576 mice), suggesting that defective UPR activation is involved in AD pathogenesis. | 119,120 |
| Parkinson’s disease | Parkin | A Parkin substrate is deposited in the ER to induce ER stress. | 121 |
| Amyotrophic lateral sclerosis | SOD1 | ER stress is induced by the aggregation of SOD1 mutants. | 122 |
| Bipolar disorder | GRP78, eIF2α, and CHOP | Dysfunction or impairment of the ER stress response is associated with decreased cellular resilience in bipolar disorder; however, the precise mechanisms of this study are lacking. | 123,124 |
| Nephrotoxicity | CHOP, caspase-12, PERK, and GRP78 | ER stress-mediated apoptosis and the inhibition of autophagy lead to nephrotoxicity. In addition, the activation of CHOP and cleavage of caspase-12 induce an ER stress response in drug-induced renal injury (e.g., paracetamol). | 125–127 |
| Type 1 diabetes | IRE1α, JNK-AP1, IL-1β, caspase-1, caspase-2, CHOP, DR5, caspase-12, and TXNIP | IRE1α-associated β cells cause damage by activating the apoptotic pathways. The JNK-AP1 and NFkB pathways exacerbate insulitis by inducing the infiltration of immune cells and activating proinflammatory genes. RIDD-mediated insulitis and β-cell death is induced by the activation of IL-1β, caspase-1, and caspase-2; β-cell death is also induced through IRE1α/JNK/CHOP/DR5 and caspase-12 activation. | 128–130 |
| Type 2 diabetes | JNK, IRS-1, and XBP1 | Obesity-induced ER stress leads to the hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1), which promotes insulin resistance. | 89,131 |
| CREB-regulated transcription coactivator 2 (CRTC2) and ATF6 | Acute increases in ER stress cause CRTC2 dephosphorylation and nuclear entry, which enhances the expression of ER quality control genes via ATF6α, and therefore, ATF6 impairs gluconeogenesis. | 132 | |
| CHOP | Hyperglycemia and free fatty acids induce β-cell death via CHOP. | 133 | |
| Diabetic cardiomyopathy | GRP78, GRP94, IRE1, ATF6, and PERK | ER stress induction by hyperglycemia, hyperlipidemia, homocysteine, or ischemia may cause cardiac inflammation/remodeling or cardiac dysfunction and cardiomyopathy. | 134 |
| Atherosclerosis | CHOP | Relevant stimuli of atherosclerosis induce macrophage death via CHOP. | 135,136 |
| CHOP | Endothelial and smooth cell death through CHOP is caused by oxidization of phospholipids, high cholesterol levels, and hyperhomocysteinemia. | 137 | |
| Liver diseases | CHOP, ATF6, IRE1, GRP78, and SREBP | Alcoholic and nonalcoholic liver diseases are known to be induced by ER stress. ER stress promotes the activation of SREBP-1c and thus promotes lipogenesis. Alcohol-induced ER stress activates CHOP-mediated apoptosis of hepatocytes. ER stress is also involved in hepatocellular carcinoma where ATF6 and IRE1 pathways, including GRP78, are involved. | 123,138 |
| Rheumatoid arthritis (RA) | IRE1α, IL-β, IL-6, and TNFα | RA boosts proinflammatory cytokines such as IL-β, IL-6, and TNFα in both infiltrated macrophages and fibroblast-like synoviocytes. IRE1α increases inflammation and angiogenesis through the mediated activation of infiltrated macrophages via toll-like receptors, and enhances synovial fibroblasts survival by upregulating ER degradation genes. | 139–142 |
| Systemic lupus erythematosus | IRE1α, JNK, XBP1s BCL-2-associated X protein, and CHOP | IRE1α/JNK/BCL-2-associated X protein and IRE1α/XBP1s/CHOP pathways lead to apoptosis in specific tissues. | 143,144 |
| Vitiligo | IRE1α, XBP1s, and TNFα | Cytokine production through IRE1α/XBP1s causes melanocyte loss. Melanocyte stem cell differentiation is inhibited by the IRE1α/XBP1s/TNFα pathway. | 145,146 |
| Inflammatory bowel disease | IRE1α, JNK, and NFκB | JNK- and NFκB-mediated cytokine production induces IRE1α to induce the secondary consequences of this disease. | 147,148 |
| Systemic sclerosis (scleroderma) | IRE1α, XBP1s, GRP78, JNK, AP1, and NFkB | The activated IRE1α/-XBP1s pathway leads to ER biogenesis, which facilitates the adaptation to an increased demand for myofibroblast protein folding. In the IRE1α/XBP1 pathway, ER chaperones such as GRP78 may contribute to efficient protein folding. The pathway degrades IRE1α/RIDD miRNA-150, a repressor of α-SMA and collagens I and IV expression, resulting in enhanced IRE1α/JNK/AP1 fibrosis, and IRE1α/NFkB pathways may involve systemic sclerosis and the expression for endothelin-1. | 149,150 |
| Viral infection | PERK, ATF6, and IRE1 | These three pathways are all involved in hepatitis C infection and HIV progression. | 151 |
| Hepatitis B virus (HBV) infection | GRP78 and PERK | Hepatitis B surface antigen stimulates the UPR through the PERK pathway and induces GRP78 expression. | 152 |
| Hepatitis C virus (HCV) infection | IRE1 and XBP1 | HCV suppresses the IRE1/XBP1 pathway to increase the synthesis of viral proteins and increase the survival of the virus in infected hepatocytes. | 153 |
| Alcoholic liver disease | GRP78, GRP94, and SREBPs | High intracellular homocysteine levels increase the expression of various UPR genes, including GRP78, GRP94, HERP, and RTP. ER stress triggers lipid biosynthesis dysregulation by activating SREBPs that lead to increased hepatic biosynthesis and cholesterol and triglyceride production. | 154 |
| Ischemia | ATF6, IRE1, PERK, and CHOP | Brain ischemia contributes to ER stress in neurons and triggers the ATF6, IRE1, and PERK pathways, leading to neuron apoptosis mediated by CHOP. | 155,156 |
| Tumorigenesis and cancers | GRP78, XBP1, CHOP, and IRE1 | GRP78 and XBP1 are involved in protective and proliferative effects in the tumor cells. The loss of CHOP production increases tumor survival in colon cancer. IRE1 mutations are involved in breast and lung malignancies. The downregulation of UPR genes is observed in prostate cancer. | 151,157,158 |
| Aging-associated diseases | UPR-related proteins | Impaired UPR, decreased cell survival, and increased apoptosis rate. | 88,115,159 |