Endoplasmic Reticulum (ER) Stress Response Failure in Diseases

Recent work provides evidence for the new terminology, 'endoplasmic reticulum (ER) stress response or sensing failure', in relation to metabolic disease. We seek to identify and amass possible conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes. Recent work provides evidence for the new terminology, 'endoplasmic reticulum (ER) stress response or sensing failure', in relation to metabolic disease. We seek to identify and amass possible conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes. ER is an important organelle found in eukaryotic cells that serves various functions, including protein synthesis, protein folding, and transporting of synthesized proteins. Its physiological perturbations affect its function, increase protein-folding demand, and accumulate unfolded/misfolded proteins inside the ER lumen, which increase ER stress and trigger the unfolded protein response (UPR) to restore cellular homeostasis. Although activation of UPR aims to restore cellular function, prolonged ER stress response can activate apoptotic signals, leading to the robust expression of downstream signaling, which damage the target cells (Figure 1A ). Indeed, increasing evidence demonstrates that metabolic disorders, such as obesity, type 2 diabetes, and age-associated pathogenesis, are associated with chronic ER stress. However, the ER stress response or sensing failure also contributes to the progression of metabolic diseases where the downstream molecules involved in ER stress responses fail to be fully activated despite the activation of the upstream ER stress sensors. A better understanding of ER stress response failure is needed to help in identifying several unknown mechanisms involved in diseases. In a recent publication in Nature Communications, Sasako et al. [1.Sasako T. et al.Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism.Nat. Commun. 2019; 10: 947Crossref PubMed Scopus (34) Google Scholar] reported that the stromal cell-derived factor 2-like 1 (Sdf2l1), an ER-resident molecule that also acts as a chaperone, is downregulated in obese and diabetic mice, which is correlated with a decrease in nuclear expression of spliced X-box binding protein 1 (sXBP1). However, inositol-requiring enzyme 1 α (IRE1α), an upstream target protein of sXBP1, is upregulated in a refeeding state. In this state, the authors suggested impaired or delayed splicing activity of IRE1α. In addition, mRNA and protein expression of downstream chaperone HSPA5 (heat shock protein family A member 5), also called BiP/GRP78 (ER chaperone binding immunoglobulin protein/glucose-regulated protein 78 kDa), is attenuated in response to obesity and diabetes. Similarly, the tendency of the phosphorylated ER stress sensor PERK (protein kinase R-like ER kinase) is high, while the downstream target phosphorylation of eIF2α (eukaryotic initiation factor 2-α-subunit) and DDIT3 (DNA damage-inducible transcript 3)/GADD153 (growth arrest- and DNA damage-inducible protein 153), or CHOP [CCAAT/enhancer-binding protein (C/EBP) homologous protein], are decreased. Furthermore, the disrupted ER-associated degradation (ERAD) was also maintained by overexpressing Sdf2l1, controlling ER proteostasis in pathological conditions. These data suggest that despite ER stress activation (as evidenced by the enhanced upstream protein), the downstream target molecules fail to be fully activated, which the authors have termed 'ER stress response failure' [1.Sasako T. et al.Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism.Nat. Commun. 2019; 10: 947Crossref PubMed Scopus (34) Google Scholar]. The relevance of ER stress response dysfunction in metabolic disorders, such as diabetes and obesity, has been demonstrated in previous studies. For example, Madhusudhan et al. demonstrated that the nuclear translocation of sXBP1 was decreased but the active form of another ER stress sensor, activating transcription factor 6 (ATF6α), was upregulated in kidneys of human and murine diabetes mellitus-induced nephropathy models, suggesting homeostatic dysfunction of UPR signaling and impaired ER homeostasis [2.Madhusudhan T. et al.Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy.Nat. Commun. 2015; 66496Crossref PubMed Scopus (114) Google Scholar]. They observed no differences in the expression of activating transcription factor 4 (ATF4), but the transcriptional target protein CHOP was highly enhanced. They demonstrated that the reduced nuclear translocation of sXBP1 in diabetic nephropathy was due to the impaired interaction of sXBP1 with p85α, a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) or the insulin receptor, leading to impaired functions of the podocytes [2.Madhusudhan T. et al.Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy.Nat. Commun. 2015; 66496Crossref PubMed Scopus (114) Google Scholar,3.Park S.W. et al.The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation.Nat. Med. 2010; 16: 429-437Crossref PubMed Scopus (226) Google Scholar]. In obese mice, a large increase in the canonical UPR sensors, like IRE1α, PERK, and ATF6α [4.Yang L. et al.S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (157) Google Scholar], together with robust expression of phosphorylated cJUN NH2-terminal kinase (p-JNK) was observed, suggesting the activation of chronic ER stress. Surprisingly, downstream signaling of IRE1α, sXBP1 was not activated, but rather was diminished in obese mice with strong expression of uXBP1 (unspliced). In addition, the target ER chaperone genes of sXBP1 were also reduced in both genetic and high-fat diet-induced obesity models. These data provide a presentiment that ER stress dysfunction or ER stress response failure is observed in several models of metabolic diseases (Box 1 and Figure 1B).Box 1Potential Factors Responsible for ER Stress Response FailureProtein–protein interactions or inter-/intra-organelle communication may determine the level of stress or the activation of UPR. Intra-ER redox imbalance, mitochondrial reactive oxygen species (ROS), redox regulation or the dysregulated calcium handling, flawed disulfide bond formation or reduction, protein aggregation, and post-translational protein modification, such as nitrosylation or glutathionylation, may have a significant role in ER stress or ER stress response failure-associated diseases [4.Yang L. et al.S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (157) Google Scholar,10.Yoboue E.D. et al.Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages.Cell Death Dis. 2018; 9331Crossref PubMed Scopus (114) Google Scholar,11.Uehara T. et al.S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.Nature. 2006; 441: 513-517Crossref PubMed Scopus (769) Google Scholar]. For example, S-nitrosylation of IRE1α or PDI increases the risk of obesity or neurodegenerative diseases, including Parkinson's or Alzheimer's disease, which are also associated with protein misfolding and aging [4.Yang L. et al.S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (157) Google Scholar,11.Uehara T. et al.S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.Nature. 2006; 441: 513-517Crossref PubMed Scopus (769) Google Scholar,12.Rizza S. et al.S-Nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E3388-E3397Crossref PubMed Scopus (104) Google Scholar]. Further studies support that the reduction in UPR function may be due to S-nitrosylation of IRE1α following impaired IRE1α ribonuclease activity, ultimately contributing to impair the IRE1α-mediated XBP1 splicing activity in obesity. Overproduction of nitric oxide induces IRE1α S-nitrosylation or PDI S-nitrosylation, which further disrupts the molecular chaperones or foldase activity or protein degradation-associated genes, amplifies the misfolded proteins by accumulating the polyubiquitinated proteins, impeding the main sensors of the ER stress response, and thus incites ER stress response failure and accelerates cell death (see Figure 1B in main text) [4.Yang L. et al.S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (157) Google Scholar,11.Uehara T. et al.S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.Nature. 2006; 441: 513-517Crossref PubMed Scopus (769) Google Scholar,13.Wang J.M. et al.IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.Sci. Signal. 2018; 11eaao4617Crossref PubMed Scopus (60) Google Scholar]. Accumulation of S-nitrosylation proteins has also been found to increase cellular senescence and aging by affecting mitochondrial homeostasis [12.Rizza S. et al.S-Nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E3388-E3397Crossref PubMed Scopus (104) Google Scholar]. Collectively, these data suggest that S-nitrosylation may cause disruption of the ER (or stress response) or mitochondrial dynamics to drive pathogenesis. Though several practices have drawn attention to identifying ER stress, the real ER stress detection sensor is still lacking in the cell biology field to study its importance to impulse pathogenesis. Protein–protein interactions or inter-/intra-organelle communication may determine the level of stress or the activation of UPR. Intra-ER redox imbalance, mitochondrial reactive oxygen species (ROS), redox regulation or the dysregulated calcium handling, flawed disulfide bond formation or reduction, protein aggregation, and post-translational protein modification, such as nitrosylation or glutathionylation, may have a significant role in ER stress or ER stress response failure-associated diseases [4.Yang L. et al.S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (157) Google Scholar,10.Yoboue E.D. et al.Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages.Cell Death Dis. 2018; 9331Crossref PubMed Scopus (114) Google Scholar,11.Uehara T. et al.S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.Nature. 2006; 441: 513-517Crossref PubMed Scopus (769) Google Scholar]. For example, S-nitrosylation of IRE1α or PDI increases the risk of obesity or neurodegenerative diseases, including Parkinson's or Alzheimer's disease, which are also associated with protein misfolding and aging [4.Yang L. et al.S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (157) Google Scholar,11.Uehara T. et al.S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.Nature. 2006; 441: 513-517Crossref PubMed Scopus (769) Google Scholar,12.Rizza S. et al.S-Nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E3388-E3397Crossref PubMed Scopus (104) Google Scholar]. Further studies support that the reduction in UPR function may be due to S-nitrosylation of IRE1α following impaired IRE1α ribonuclease activity, ultimately contributing to impair the IRE1α-mediated XBP1 splicing activity in obesity. Overproduction of nitric oxide induces IRE1α S-nitrosylation or PDI S-nitrosylation, which further disrupts the molecular chaperones or foldase activity or protein degradation-associated genes, amplifies the misfolded proteins by accumulating the polyubiquitinated proteins, impeding the main sensors of the ER stress response, and thus incites ER stress response failure and accelerates cell death (see Figure 1B in main text) [4.Yang L. et al.S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.Science. 2015; 349: 500-506Crossref PubMed Scopus (157) Google Scholar,11.Uehara T. et al.S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.Nature. 2006; 441: 513-517Crossref PubMed Scopus (769) Google Scholar,13.Wang J.M. et al.IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.Sci. Signal. 2018; 11eaao4617Crossref PubMed Scopus (60) Google Scholar]. Accumulation of S-nitrosylation proteins has also been found to increase cellular senescence and aging by affecting mitochondrial homeostasis [12.Rizza S. et al.S-Nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E3388-E3397Crossref PubMed Scopus (104) Google Scholar]. Collectively, these data suggest that S-nitrosylation may cause disruption of the ER (or stress response) or mitochondrial dynamics to drive pathogenesis. Though several practices have drawn attention to identifying ER stress, the real ER stress detection sensor is still lacking in the cell biology field to study its importance to impulse pathogenesis. Obesity and diabetes are among several age-associated diseases, and a similar type of UPR impairment or a kind of ER stress response failure has also been observed in aging. Aging is a process that involves a very complex mechanism [5.Lopez-Otin C. et al.The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (7830) Google Scholar], accompanied by the declining capacity of the cellular machinery, which leads to misfolded and aggregated proteins, resulting in cell death. Aging has been attributed to mitochondrial dysfunction. However, recent studies have explored the ER stress signaling cascade and quality control of the ER, including ER stress response failure, in the process of aging. A previous study described that in aging (22–24-month-old) mouse cerebral cortex, BiP/GRP78 expression was decreased compared with young (10-week-old) mice [6.Naidoo N. et al.Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling.J. Neurosci. 2008; 28: 6539-6548Crossref PubMed Scopus (216) Google Scholar]. The ER stress signaling pathway PERK was also disturbed, having a reduced expression of phosphorylation of PERK and eIF2α and a high activation of CHOP. Moreover, cleavage of caspase-12 was clearly observed in the aging mice, suggesting the activation of ER stress-mediated apoptosis signaling. Relative to young mice, highly aggregated ubiquitin molecules in the aging cerebral cortex were observed. This reveals the presence of highly misfolded proteins in aging mice, suggesting the disruption of the ubiquitin–proteasome system or ERAD to eliminate the misfolded or unfolded proteins [6.Naidoo N. et al.Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling.J. Neurosci. 2008; 28: 6539-6548Crossref PubMed Scopus (216) Google Scholar,7.Higuchi-Sanabria R. et al.A futile battle? Protein quality control and the stress of aging.Dev. Cell. 2018; 44: 139-163Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. Loss of ERAD may not maintain the ER-resident proteins and diminishes quality control, while autophagy, involved in clearing the misfolded proteins, may also get affected during the aging process [7.Higuchi-Sanabria R. et al.A futile battle? Protein quality control and the stress of aging.Dev. Cell. 2018; 44: 139-163Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. This further suggests that activities of major proteolytic systems, such as ubiquitin–proteasome or autophagy–lysosomal systems, decline and directly affect the protein quality control during aging [5.Lopez-Otin C. et al.The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (7830) Google Scholar,7.Higuchi-Sanabria R. et al.A futile battle? Protein quality control and the stress of aging.Dev. Cell. 2018; 44: 139-163Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. These data indicate that the diminished protein quality control compromised the adaptive function of the UPR, leading to activation of apoptotic pathways, though following the same ER stress signaling pathway during the aging process. Although there are several discrepancies observed in the expression of UPR elements in aging [8.Estebanez B. et al.Endoplasmic reticulum unfolded protein response, aging and exercise: an update.Front. Physiol. 2018; 9: 1744Crossref PubMed Scopus (53) Google Scholar,9.Hernandez-Segura A. et al.Hallmarks of cellular senescence.Trends Cell Biol. 2018; 28: 436-453Abstract Full Text Full Text PDF PubMed Scopus (931) Google Scholar], most of the studies suggest that UPR impairment or aberrant ER stress signaling is observed during the aging process. The adaptive proteins and chaperones, such as BiP and protein disulfide isomerase (PDI), were disrupted and declined, while proapoptotic proteins, such as CHOP or caspases, were highly upregulated in the aging conditions. UPR has a dual role and can adapt and follow a survival pathway as well as an apoptotic pathway under chronic stress. Therefore, the activation of aberrant ER stress and impaired ER proteostasis in aging resembles ER stress sensing failure, which could be deleterious to cellular health (Figure 1B). In addition to the aforementioned factors, other contributing factors to ER stress response failure are described in Box 1. Based on the earlier evidence, we can generalize future investigations that need to be performed. Do all three branches of the UPR need to be triggered during ER stress conditions? Does the activation of upstream signaling molecules also induce ER stress despite downstream activation? What could be expected for cellular fate if only upstream ER stress sensors are activated? What are the possible differences in cellular conditions between the canonical ER stress and ER stress sensing failure-mediated ER stress? The in vitro or in vivo model could be challenging in aspect to study these types of phenotypes. More research is required to show consistency regarding ER stress response/sensing failure in pathological conditions. This research was supported by the Korean National Research Foundation (2017R1E1A1A01073796, 2017M3A9G7072719, and NRF-2017M3A9E4047243), Republic of Korea.