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(definition) 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 re