bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒04‒04
eleven papers selected by
Susan Logue
University of Manitoba

  1. Cell Struct Funct. 2021 Mar 26.
      Dysfunction of the endoplasmic reticulum (ER), so-called ER stress, is accompanied with accumulation of unfolded proteins in the ER. Eukaryotic cells commonly have an ER-located transmembrane protein, Ire1, which triggers cellular protective events against ER stress. In animal cells, PERK and ATF6 also initiate the ER-stress response. As a common strategy to control the activity of these ER-stress sensors, an ER-resident molecular chaperone, BiP, serves as their negative regulator, and dissociates from them in response to ER stress. Although it sounds reasonable that unfolded proteins and Ire1 compete for BiP association, some publications argue against this competition model. Moreover, yeast Ire1 (and possibly also the mammalian major Ire1 paralogue IRE1α) directly detects ER-accumulated unfolded proteins, and subsequently oligomerizes for its further activation. Apart from protein misfolding, the saturation of membrane phospholipids is another outcome of ER-stressing stimuli, which is sensed by the transmembrane domain of Ire1. This review describes the canonical and up-to-date insights concerning stress-sensing and regulatory mechanisms of yeast Ire1 and metazoan ER-stress sensors.Key words: endoplasmic reticulum, stress, unfolded protein response, molecular chaperone.
    Keywords:  endoplasmic reticulum; molecular chaperone; stress; unfolded protein response
  2. Microorganisms. 2021 Mar 29. pii: 705. [Epub ahead of print]9(4):
      The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.
    Keywords:  ER stress; UPR; bacteria; effector proteins; infection; secretion systems
  3. Biomaterials. 2021 Mar 24. pii: S0142-9612(21)00113-7. [Epub ahead of print]272 120757
      Transplantation is the most effective, and sometimes the only resort for end-stage organ failure. However, allogeneic graft suffers greatly from lymphocyte-mediated immunorejection, which bears close relationship with a hyperactivation of endoplasmic reticulum (ER) stress response in host lymphocytes, especially in CD8+ T cells (T-8). Therefore, regulating lymphocytic ER unfolded protein response (UPR) might be a potential therapeutic breakthrough in alleviating graft rejection. Here, ER-targetable liposome is prepared via the surface modification of ER-targeting peptide (Pardaxin), which efficiently loads and directly delivers small molecule inhibitor of UPR sensor IRE1α into the ER of lymphocytes, inducing a systemic immunosuppression that facilitates tumorigenesis and metastasis in the tumor inoculation challenge in vivo. And in vitro, a stage-differential dependency of IRE1α in the phase transition of T-8 is identified. Specifically, inhibiting IRE1α at the early responding stages of T-8, especially at the activation phase, results in a shrunk proliferation, impaired effector function, and limited memory commitment, which might contribute centrally to the induced overall immunosuppression. Based on this, a classical acute rejection model, murine full-thickness trunk skin allograft that primary arises from the hyperactivity of T-lymphocyte, is used. Results suggest that lymphocytic IRE1α inactivation attenuates transplant rejection and prolongs graft survival, with a limited effector function and memory commitment of host T-8. Moreover, an even higher immunosuppressive effect is obtained when IRE1α inhibition is used in combination with immunosuppressant tacrolimus (FK506), which might owe to a synergistic regulation of inflammatory transcription factors. These findings provide a deeper insight into the biological polarization and stress response of lymphocytes, which might guide the future development of allogeneic transplantation.
    Keywords:  Allograft rejection; CD8(+) T cells; ER-targeting; IRE1α; Immunosuppression; Lymphocyte
  4. Pharmaceuticals (Basel). 2021 Mar 08. pii: 232. [Epub ahead of print]14(3):
      Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M-ZDF and M-ZL) or vehicle (C-ZDF and C-ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C-ZL rats, higher ER stress response associated with impaired renal morphology was observed in C-ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho-protein kinase RNA-like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho-c-jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.
    Keywords:  diabesity; endoplasmic reticulum stress; kidney; melatonin
  5. G3 (Bethesda). 2021 Mar 30. pii: jkab095. [Epub ahead of print]
      Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Approximately 90% of these 385 genes are conserved in humans, and one third of the conserved genes have been implicated in human disease. Furthermore, many have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. Our dataset primarily contains mitochondrial enhancers and non-mitochondrial suppressors of UPRmt, indicating that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function, which, when disrupted, can be compensated for by many different cellular processes. Analysis of the subsets 'non-mitochondrial enhancers' and 'mitochondrial suppressors' suggests that organellar contact sites, especially between the ER and mitochondria, are of importance for mitochondrial homeostasis. In addition, we identified several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants and found a potential link between pre-mRNA splicing and UPRmt activation.
    Keywords:  IP3 signaling; Mitoguardin; fzo-1; mitochondrial dynamics; mitochondrial unfolded protein response
  6. Cells. 2021 Mar 30. pii: 755. [Epub ahead of print]10(4):
      Despite multiple research studies regarding metabolic syndrome and diabetes, the full picture of their molecular background and pathogenies remains elusive. The latest studies revealed that sex hormone-binding globulin (SHBG)-a serum protein released mainly by the liver-may participate in metabolic dysregulation, as its low serum level correlates with a risk for obesity, metabolic syndrome, and diabetes. Yet, the molecular phenomenon linking SHBG with these disorders remains unclear. In the presented study, we investigate how exogenous SHBG affects metabolically impaired hepatocytes with special attention to endoplasmic reticulum stress (ER stress) and lipid metabolism both in vitro and ex vivo. For that reason, palmitate-treated HepG2 cells and liver tissue samples collected post mortem were cultured in the presence of 50 nM and 100 nM SHBG. We found that SHBG protects against ER stress development and its progression. We have found that SHBG decreased the expression levels of inositol-requiring enzyme 1 (IRE1α), activating transcription factor 6 (ATF6), DNA damage-inducible transcript 3 (CHOP), and immunoglobulin heavy chain-binding protein (BIP). Furthermore, we have shown that it regulates lipolytic gene expression ex vivo. Additionally, herein, we deliver a novel large-animal model to study SHBG in translational research. Our data provide new insights into the cellular and molecular mechanisms by which SHBG modulates hepatocyte metabolism and offer a new experimental approach to study SHBG in human diseases.
    Keywords:  SHBG; endoplasmic reticulum stress; liver; metabolic syndrome; sex hormone binding globulin
  7. Endocr Metab Sci. 2021 Jun 30. pii: 100092. [Epub ahead of print]3
      Recent evidence suggest that the endothelial barrier function is enhanced by the mild activation of the unfolded protein response (UPR), which aims to suppress abnormal increases of endoplasmic reticulum stress. Heat shock protein 90 inhibitors and growth hormone releasing hormone antagonists exert the capacity to activate this multifaceted cellular mechanism (UPR). Thus, investigations on the signalling network involved in those events, may deliver exciting opportunities in diseases related to endothelial barrier dysfunction. The diverse spectrum of those pathologies include sepsis and Acute Respiratory Distress Syndrome (ARDS).
    Keywords:  Acute Lung Injury; Acute Respiratory Distress Syndrome; Inflammation; P53; Sepsis
  8. Free Radic Biol Med. 2021 Mar 30. pii: S0891-5849(21)00191-X. [Epub ahead of print]
      Hyperoxaluria is one of the leading causes of calcium oxalate stone formation in the kidney. Since hyperoxaluria produces Endoplasmic Reticulum (ER) stress in the kidney, it is thus likely that the adaptive unfolded protein response might affect the mitochondrial population as ER and mitochondria share close physical and functional interactions mandatory for several biological processes. Thus this work was designed to study the putative effects of endoplasmic reticulum stress on the renal mitochondria during hyperoxaluria-induced nephrolithiasis. The results showed that hyperoxaluria induced an ER stress led to the unfolded protein response in the renal tissue of experimental rats. Hampered mitochondrion functioning was detected with decreased mitochondrial membrane potential and upsurged mitochondria calcium. These changes in the mitochondria function and ER stress are preceded by apoptosis. The expression of Sigma-1 receptor protein found in the Mitochondria associated ER membranes, the connecting link between ER and mitochondria was found to decrease in the hyperoxaluric rats. Inhibition of ER stress by 4-Phenylbutyric acid prevented the decrease in mitochondria membrane potential and increase in mitochondria calcium observed in hyperoxaluric rats. Also, it restored the protein expression of the sigma-1 receptor protein. On the other hand, N-acetyl cysteine had a nominal impact on the reduction of the ER stress-induced mitochondrial dysfunction. In conclusion, our data showed that hyperoxaluria induces renal ER stress which triggers mitochondria dysfunction, might be via alteration in the sigma-1 receptor protein in the mitochondria-associated ER membranes, which leads to apoptosis, renal injury, and calcium oxalate crystal deposition.
    Keywords:  4-Phenyl butyric acid; Endoplasmic reticulum; Hyperoxaluria; Mitochondria; Nephrolithiasis; Oxidative stress
  9. Cancers (Basel). 2021 Mar 10. pii: 1198. [Epub ahead of print]13(6):
      Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.
    Keywords:  EGFRvIII; ER stress; RCN1; apoptosis; glioblastoma
  10. Int J Mol Sci. 2021 Mar 17. pii: 3063. [Epub ahead of print]22(6):
      New anti-inflammatory treatments are needed for CF airway disease. Studies have implicated the endoplasmic reticulum stress transducer inositol requiring enzyme 1α (IRE1α) in CF airway inflammation. The activation of IRE1α promotes activation of its cytoplasmic kinase and RNase, resulting in mRNA splicing of X-box binding protein-1 (XBP-1s), a transcription factor required for cytokine production. We tested whether IRE1α kinase and RNase inhibition decreases cytokine production induced by the exposure of primary cultures of homozygous F508del CF human bronchial epithelia (HBE) to supernatant of mucopurulent material (SMM) from CF airways. We evaluated whether IRE1α expression is increased in freshly isolated and native CF HBE, and couples with increased XBP-1s levels. A FRET assay confirmed binding of the IRE1α kinase and RNase inhibitor, KIRA6, to the IRE1α kinase. F508del HBE cultures were exposed to SMM with or without KIRA6, and we evaluated the mRNA levels of XBP-1s, IL-6, and IL-8, and the secretion of IL-6 and IL-8. IRE1α mRNA levels were up-regulated in freshly isolated CF vs. normal HBE and coupled to increased XBP-1s mRNA levels. SMM increased XBP-1s, IL-6, and IL-8 mRNA levels and up-regulated IL-6 and IL-8 secretion, and KIRA6 blunted these responses in a dose-dependent manner. Moreover, a triple combination of CFTR modulators currently used in the clinic had no effect on SMM-increased XBP-1s levels coupled with increased cytokine production in presence or absence of KIRA6. These findings indicate that IRE1α mediates cytokine production in CF airways. Small molecule IRE1α kinase inhibitors that allosterically reduce RNase-dependent XBP-1s may represent a new therapeutic strategy for CF airway inflammation.
    Keywords:  CFTR modulators; KIRA6; airway epithelia; airway inflammation; cystic fibrosis; cytokine; inositol requiring enzyme 1α; unfolded protein response
  11. Cell Rep. 2021 Mar 30. pii: S2211-1247(21)00236-9. [Epub ahead of print]34(13): 108922
      Hematopoietic stem cells (HSCs) regenerate blood cells upon hematopoietic injuries. During homeostasis, HSCs are maintained in a low reactive oxygen species (ROS) state to prevent exhaustion. However, the role of nitric oxide (NO) in controlling HSC regeneration is still unclear. Here, we find increased NO during HSC regeneration with an accumulation of protein aggregation. S-nitrosoglutathione reductase (GSNOR)-deleted HSCs exhibit a reduced reconstitution capacity and loss of self-renewal after chemotherapeutic injury, which is resolved by inhibition of NO synthesis. Deletion of GSNOR enhances protein S-nitrosylation, resulting in an accumulation of protein aggregation and activation of unfolded protein response (UPR). Treatment of taurocholic acid (TCA), a chemical chaperone, rescues the regeneration defect of Gsnor-/- HSCs after 5-fluorouracil (5-FU) treatment. Deletion of C/EBP homologous protein (Chop) restores the reconstitution capacity of Gsnor-/- HSCs. These findings establish a link between S-nitrosylation and protein aggregation in HSC in the context of blood regeneration.
    Keywords:  GSNOR; S-nitrosylation; hematopoietic stem cell; nitric oxide; protein aggregation; regeneration