bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒01‒31
eleven papers selected by
Susan Logue
University of Manitoba


  1. Mol Metab. 2021 Jan 20. pii: S2212-8778(21)00009-0. [Epub ahead of print] 101169
    Lemmer IL, Willemsen N, Hilal N, Bartelt A.
      BACKGROUND: The global rise of metabolic disorders, such as obesity, diabetes type 2 and cardiovascular disease, demands a thorough molecular understanding of the cellular mechanisms that govern health or disease. The endoplasmic reticulum (ER) is a key organelle for cellular function and metabolic adaptation and, therefore, disturbed ER function, "ER stress", is a key feature of metabolic disorders.SCOPE OF REVIEW: As ER stress remains an ill-defined phenomenon, this review provides a general guide to understanding the nature, aetiology and consequences of ER stress in metabolic disorders. We define ER stress by its type of stressor, which is driven by proteotoxicity, lipotoxicity, and/or glucotoxicity. We discuss the implications of ER stress in metabolic disorders by reviewing evidence implicating ER phenotypes and organelle communication, protein quality control, calcium homeostasis, lipid and carbohydrate metabolism, and inflammation as key mechanisms in the development of ER stress and metabolic dysfunction.
    MAJOR CONCLUSIONS: In mammalian biology, ER is a phenotypically and functionally diverse platform for nutrient sensing, which is critical for cell-type specific metabolic control by e.g. hepatocytes, adipocytes, muscle cells, and neurons. In these cells, ER stress is a distinct, transient state of functional imbalance, which is usually resolved by the activation of adaptive programs such as the unfolded protein response (UPR), ER-associated protein degradation (ERAD), or autophagy. However, challenges to proteostasis also impact lipid and glucose metabolism and vice versa. In the ER, both sensing and adaptive measures are integrated and failure of the ER to adapt leads to aberrant metabolism, organelle dysfunction, insulin resistance, and inflammation. In conclusion, the ER is intricately linked to a wide spectrum of cellular functions and is a critical component in maintaining and restoring metabolic health.
    Keywords:  ERAD; NFE2L1; Obesity; UPR; UPS; autophagy; calcium homeostasis; diabetes; endoplasmic reticulum; glucotoxicity; inflammation; lipid metabolism; lipotoxicity; proteostasis; proteotoxicity
    DOI:  https://doi.org/10.1016/j.molmet.2021.101169
  2. Sci Signal. 2021 Jan 26. pii: eabb3616. [Epub ahead of print]14(667):
    Shimizu T, Higashijima Y, Kanki Y, Nakaki R, Kawamura T, Urade Y, Wada Y.
      Pulmonary arterial hypertension (PAH) is a fatal disease characterized by excessive pulmonary vascular remodeling. However, despite advances in therapeutic strategies, patients with PAH bearing mutations in the bone morphogenetic protein receptor type 2 (BMPR2)-encoding gene present severe phenotypes and outcomes. We sought to investigate the effect of PER-like kinase (PERK), which participates in one of three major pathways associated with the unfolded protein response (UPR), on PAH pathophysiology in BMPR2 heterozygous mice. BMPR2 heterozygosity in pulmonary artery smooth muscle cells (PASMCs) decreased the abundance of the antiapoptotic microRNA miR124-3p through the arm of the UPR mediated by PERK. Hypoxia promoted the accumulation of unfolded proteins in BMPR2 heterozygous PASMCs, resulting in increased PERK signaling, cell viability, cellular proliferation, and glycolysis. Proteomic analyses revealed that PERK ablation suppressed PDGFRβ-STAT1 signaling and glycolysis in hypoxic BMPR2 heterozygous PASMCs. Furthermore, PERK ablation or PERK inhibition ameliorated pulmonary vascular remodeling in the Sugen/chronic hypoxia model of PAH, irrespective of BMPR2 status. Hence, these findings suggest that PERK inhibition is a promising therapeutic strategy for patients with PAH with or without BMPR2 mutation.
    DOI:  https://doi.org/10.1126/scisignal.abb3616
  3. J Pharmacol Exp Ther. 2021 Jan 29. pii: JPET-AR-2020-000417. [Epub ahead of print]
    Zhang L, Kim SH, Park KH, Townsend D, Tew KD.
      We have created a novel glutathione S-transferase Pi 1 (gstp1) knockout (KO) zebrafish model and used it for comparative analyses of redox homeostasis, response to drugs that cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). Under basal conditions, gstp1 KO larvae had higher expression of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) accompanied by a more reduced larval environment and a status consistent with reductive stress. Compared to wild type (WT), various UPR markers were decreased in KO larvae, but treatment with drugs that induce ER stress caused greater toxicities and increased expression of Nrf2 and UPR markers in KO; tunicamycin (TuM) and 02-{2,4-dinitro-5-[4-(N-methylamino) benzoyloxy] phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate (PABA/NO) activated IRE1/XBP1 pathways, while thapsigargin (ThG) caused greater activation of PERK/ATF4/CHOP pathways. These results suggest that this teleost model is useful in predicting how GSTP regulates organismal management of oxidative/reductive stress and is a determinant of response to drug-induced ER stress and the UPR. Significance Statement A new zebrafish model has been created to study the importance of Gstp1 in development, redox homeostasis and response to drugs that enact cytotoxicity through ER-stress and induction of the UPR.
    Keywords:  Endoplasmic reticulum stress; Gene editing/CRISPR; Glutathione S-transferase (GST)
    DOI:  https://doi.org/10.1124/jpet.120.000417
  4. Biomedicines. 2021 Jan 27. pii: 118. [Epub ahead of print]9(2):
    Gonnella R, Gilardini Montani MS, Guttieri L, Romeo MA, Santarelli R, Cirone M.
      Primary Effusion Lymphoma (PEL) is a highly aggressive B cell lymphoma associated with Kaposi's Sarcoma-associated Herpesvirus (KSHV). It is characterized by a high level of basal Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR) activation and constitutive phosphorylation of oncogenic pathways such as the Signal Transducer and activator of Transcription (STAT3). In this study, we found that the inositol requiring kinase (IRE) 1alpha/X-box binding protein (XBP1) axis of UPR plays a key role in the survival of PEL cells, while double stranded RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor (ATF) 6 slightly influence it, in correlation with the capacity of the IRE1alpha/XBP1 axis to induce the release of interleukin (IL)-6, IL-10 and Vascular-Endothelial Growth Factor (VEGF). Moreover, we found that IRE1alpha/XBP1 inhibition reduced STAT3 Tyr705 phosphorylation and induced a pro-survival autophagy in PEL cells. In conclusion, this study suggests that targeting the IRE1alpha/XBP1 axis represents a promising strategy against PEL cells and that the cytotoxic effect of this treatment may be potentiated by autophagy inhibition.
    Keywords:  ER stress; IRE1 alpha; STAT3; UPR; XBP1; cytokines
    DOI:  https://doi.org/10.3390/biomedicines9020118
  5. Biol Open. 2021 Jan 25. pii: bio.057992. [Epub ahead of print]
    Bhoi A, Palladino F, Fabrizio P.
      Auxins are plant growth regulators that influence most aspects of plant development through complex mechanisms. The development of an auxin-inducible degradation (AID) system has enabled rapid, conditional protein depletion in yeast and cultured cells. More recently, the system was successfully adapted to C. elegans to achieve auxin-dependent degradation of targets in all tissues and developmental stages. Whether auxin treatment alone has an impact on nematode physiology is an open question. Here we show that indole-3-acetic acid (IAA), the auxin most commonly used to trigger AID in worms, functions through the conserved IRE-1/XBP-1 branch of the Unfolded Protein Response (UPR) to promote resistance to Endoplasmic Reticulum (ER) stress. Because the UPR not only plays a central role in restoring ER homeostasis, but also promotes lipid biosynthesis and regulates lifespan, we suggest that extreme caution should be exercised when using the AID system to study these and related processes.
    Keywords:  Auxin; ER stress; Tunicamycin; Unfolded Protein Response
    DOI:  https://doi.org/10.1242/bio.057992
  6. Trends Biochem Sci. 2021 Jan 25. pii: S0968-0004(20)30325-X. [Epub ahead of print]
    Ferro-Novick S, Reggiori F, Brodsky JL.
      Lysosomal degradation of endoplasmic reticulum (ER) fragments by autophagy, termed ER-phagy or reticulophagy, occurs under normal as well as stress conditions. The recent discovery of multiple ER-phagy receptors has stimulated studies on the roles of ER-phagy. We discuss how the ER-phagy receptors and the cellular components that work with these receptors mediate two important functions: ER homeostasis and ER quality control. We highlight that ER-phagy plays an important role in alleviating ER expansion induced by ER stress, and acts as an alternative disposal pathway for misfolded proteins. We suggest that the latter function explains the emerging connection between ER-phagy and disease. Additional ER-phagy-associated functions and important unanswered questions are also discussed.
    Keywords:  autophagy receptor; endoplasmic reticulum; human disease; macro-ER-phagy; micro-ER-phagy; proteostasis; reticulophagy
    DOI:  https://doi.org/10.1016/j.tibs.2020.12.013
  7. Cell Death Discov. 2021 Jan 26. 7(1): 24
    Muthuraj PG, Sahoo PK, Kraus M, Bruett T, Annamalai AS, Pattnaik A, Pattnaik AK, Byrareddy SN, Natarajan SK.
      Zika virus (ZIKV) infection to a pregnant woman can be vertically transmitted to the fetus via the placenta leading to Congenital Zika syndrome. This is characterized by microcephaly, retinal defects, and intrauterine growth retardation. ZIKV induces placental trophoblast apoptosis leading to severe abnormalities in the growth and development of the fetus. However, the molecular mechanism behind ZIKV-induced apoptosis in placental trophoblasts remains unclear. We hypothesize that ZIKV infection induces endoplasmic reticulum (ER) stress in the trophoblasts, and sustained ER stress results in apoptosis. HTR-8 (HTR-8/SVneo), a human normal immortalized trophoblast cell and human choriocarcinoma-derived cell lines (JEG-3 and JAR) were infected with ZIKV. Biochemical and structural markers of apoptosis like caspase 3/7 activity and percent apoptotic nuclear morphological changes, respectively were assessed. ZIKV infection in placental trophoblasts showed an increase in the levels of CHOP mRNA and protein expression, which is an inducer of apoptosis. Next, we also observed increased levels of ER stress markers such as phosphorylated forms of inositol-requiring transmembrane kinase/endoribonuclease 1α (P-IRE1α), and its downstream target, the spliced form of XBP1 mRNA, phosphorylated eukaryotic initiation factor 2α (P-eIF2α), and activation of cJun N-terminal Kinase (JNK) and p38 mitogen activated protein kinase (MAPK) after 16-24 h of ZIKV infection in trophoblasts. Inhibition of JNK or pan-caspases using small molecule inhibitors significantly prevented ZIKV-induced apoptosis in trophoblasts. Further, JNK inhibition also reduced XBP1 mRNA splicing and viral E protein staining in ZIKV infected cells. In conclusion, the mechanism of ZIKV-induced placental trophoblast apoptosis involves the activation of ER stress and JNK activation, and the inhibition of JNK dramatically prevents ZIKV-induced trophoblast apoptosis.
    DOI:  https://doi.org/10.1038/s41420-020-00379-8
  8. Cell Signal. 2021 Jan 20. pii: S0898-6568(21)00010-3. [Epub ahead of print] 109922
    Gupta S, Mishra A, Singh S.
      The study was conducted to assess the role of eukaryotic initiation factor 2 (eIF2α) in progressive dopaminergic neuronal death employing various interventions (YM08, 4μ8C, AEBSF, salubrinal, ursolic acid) of endoplasmic reticulum (ER) stress signaling. The protein level of all the ER stress related signaling factors (GRP78, IRE1α, ATF6, eIF2α, ATF4, XBP-1, GADD153) were estimated after 3 and 7 day of experiment initiation. Findings with single administration of interventions showed that salubrinal exhibited significant protection against rotenone induced adverse alterations in comparison to other interventions. Therefore, further study was expanded with repeat dose of salubrinal. Rotenone administration in rat brain caused the significant biochemical alterations, dose dependent progressive neuronal apoptosis and altered neuronal morphology which was significantly attenuated with salubrinal treatment. In conclusion, findings showed that rotenone administration caused the dose dependent progressive neuronal death including cardinal role of eIF2α, suggesting the potential pharmacological utilization of salubrinal or salubrinal like molecules in therapeutics of Parkinson's diseases.
    Keywords:  Apoptosis; Endoplasmic reticulum stress; Parkinson's disease; Salubrinal; eIF2α
    DOI:  https://doi.org/10.1016/j.cellsig.2021.109922
  9. Plant Sci. 2021 Feb;pii: S0168-9452(20)30364-2. [Epub ahead of print]303 110758
    Li Z, Howell SH.
      IRE1 is a key factor in the Unfolded Protein Response (UPR) in plants. IRE1 is a single-pass transmembrane protein that has a lumenal domain (LD) and cytoplasmic domain (CD), which perform quite different tasks on different sides of the ER membrane. The LD recognizes the presence of misfolded proteins in the ER lumen. The LDs of IRE1 in different plant species are predicted to fold into β-propeller structures with surfaces for protein-protein interactions. Likewise, the CDs of plant IRE1s have predicted structural interfaces that promote the face-to-face arrangements of IRE1 for transphosphorylation and back-to-back arrangements for RNA splicing. Hence, the structures on the different faces of plant IRE1s have unique features for recognizing problems of protein folding in the ER and transducing that signal to activate the UPR.
    Keywords:  INOSITOL REQUIRING FACTOR 1; Messenger RNA splicing; Regulated IRE1-Dependent RNA Decay; Unfolded protein response; bZIP60
    DOI:  https://doi.org/10.1016/j.plantsci.2020.110758
  10. J Biol Chem. 2021 Jan 23. pii: S0021-9258(21)00106-X. [Epub ahead of print] 100335
    Eiyama A, Aaltonen MJ, Nolte H, Tatsuta T, Langer T.
      Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle phosphatidic acid (PA) mainly synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the cardiolipin synthase Crd1, Ups1 deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1Δ cells leads to altered unfolded protein response (UPR) and mTORC1 signaling, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine (PC) and a reduced phosphatidylethanolamine (PE)/PC ratio in the ER of ups1Δ cells which suppresses the UPR. Moreover, we observed inhibition of TORC1 signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the SEACIT complex, increased cytosolic protein synthesis and restored glycolytic growth of ups1Δ cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.
    Keywords:  Mitochondria; PRELID1; TORC1; Ups1; endoplasmic reticulum (ER); lipid transfer; phospholipid; unfolded protein response (UPR); yeast
    DOI:  https://doi.org/10.1016/j.jbc.2021.100335
  11. Biomedicines. 2021 Jan 20. pii: E96. [Epub ahead of print]9(2):
    Szász I, Koroknai V, Patel V, Hajdú T, Kiss T, Ádány R, Balázs M.
      HA15 is a new anti-melanoma drug that triggers endoplasmic reticulum (ER) stress and causes deleterious effects on melanoma cell viability due to autophagy and apoptosis, regardless of driver mutations or drug resistance. In this study, we investigated the effect of HA15 on the viability/proliferation of BRAFV600E-mutant melanoma cells using different culture conditions. In contrast to the published data, we did not detect significant melanoma cell death under normal culture conditions using HA15 treatment. Indeed, only cells that were cultured under long-term starvation conditions were sensitive to the drug. Quantitative measurements of ER stress and autophagy markers showed that the compound HA15 does not trigger stress alone but synergistically enhances ER stress under starvation conditions. Importantly, we observed that the viability of normal melanocytes decreased significantly with treatment, even at low HA15 concentrations. Finally yet importantly, we were able to generate HA15-resistant cell lines, which failed by Cerezo et al. In summary, HA15 only influences the viability of cells that are starved for several hours before and during treatment. However, this in vitro setting is far from the in vivo conditions. In addition, our data clearly show that melanoma cells can acquire HA15 resistance. Further studies are needed to prove that HA15 is an effective anti-cancer agent.
    Keywords:  ER stress; HA15 anti-melanoma drug; RNA-Seq; apoptosis; autophagy; resistant cell lines
    DOI:  https://doi.org/10.3390/biomedicines9020096