bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–08–14
twelve papers selected by
Susan Logue, University of Manitoba
  1. Adaptation to chronic ER stress enforces pancreatic β-cell plasticity.
  2. A Pipeline for Natural Small Molecule Inhibitors of Endoplasmic Reticulum Stress.
  3. QM/MM Well-Tempered Metadynamics Study of the Mechanism of XBP1 mRNA Cleavage by Inositol Requiring Enzyme 1α RNase.
  4. The role of endoplasmic reticulum stress in the regulation of long noncoding RNAs in cancer.
  5. Evolutionary Aspects of the Unfolded Protein Response.
  6. Newly synthesized mRNA escapes translational repression during the acute phase of the mammalian unfolded protein response.
  7. Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma.
  8. Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
  9. Regulation and Functions of the ER-Associated Nrf1 Transcription Factor.
  10. The Role of the Rhomboid Superfamily in ER Protein Quality Control: From Mechanisms and Functions to Diseases.
  11. ER-Phagy: Quality and Quantity Control of the Endoplasmic Reticulum by Autophagy.
  12. The endoplasmic reticulum membrane complex promotes proteostasis of GABAA receptors.
  1. Nat Commun. 2022 Aug 08. 13(1): 4621
    Adaptation to chronic ER stress enforces pancreatic β-cell plasticity.
    Chien-Wen Chen, Bo-Jhih Guan, Mohammed R Alzahrani, Zhaofeng Gao, Long Gao, Syrena Bracey, Jing Wu, Cheikh A Mbow, Raul Jobava, Leena Haataja, Ajay H Zalavadia, Ashleigh E Schaffer, Hugo Lee, Thomas LaFramboise, Ilya Bederman, Peter Arvan, Clayton E Mathews, Ivan C Gerling, Klaus H Kaestner, Boaz Tirosh, Feyza Engin, Maria Hatzoglou.
      Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-022-32425-7
  2. Front Pharmacol. 2022 ;13 956154
    A Pipeline for Natural Small Molecule Inhibitors of Endoplasmic Reticulum Stress.
    Daniela Correia da Silva, Patrícia Valentão, Paula B Andrade, David M Pereira.
      The homeostasis of eukaryotic cells is inseverable of that of the endoplasmic reticulum (ER). The main function of this organelle is the synthesis and folding of a significant portion of cellular proteins, while it is also the major calcium reservoir of the cell. Upon unresolved ER stress, a set of stress response signaling pathways that are collectively labeled as the unfolded protein response (UPR) is activated. Prolonged or intense activation of this molecular machinery may be deleterious. It is known that compromised ER homeostasis, and consequent UPR activation, characterizes the pathogenesis of neurodegenerative diseases. In an effort to discover new small molecules capable of countering ER stress, we subjected a panel of over 100 natural molecules to a battery of assays designed to evaluate several hallmarks of ER stress. The protective potential of these compounds against ER stress was evaluated at the levels of calcium homeostasis, key gene and protein expression, and levels of protein aggregation in fibroblasts. The most promising compounds were subsequently tested in neuronal cells. This framework resulted in the identification of several bioactive molecules capable of countering ER stress and deleterious events associated to it. Delphinidin stands out as the most promising candidate against neurodegeneration. This compound significantly inhibited the expression of UPR biomarkers, and displayed a strong potential to inhibit protein aggregation in the two aforementioned cell models. Our results indicate that natural products may be a valuable resource in the development of an effective therapeutic strategy against ER stress-related diseases.
    Keywords:  drug discovery; endoplasmic reticulum stress; natural products; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.3389/fphar.2022.956154
  3. J Chem Inf Model. 2022 Aug 12.
    QM/MM Well-Tempered Metadynamics Study of the Mechanism of XBP1 mRNA Cleavage by Inositol Requiring Enzyme 1α RNase.
    Sayyed Jalil Mahdizadeh, Emil Pålsson, Antonio Carlesso, Eric Chevet, Leif A Eriksson.
      A range of in silico methodologies were herein employed to study the unconventional XBP1 mRNA cleavage mechanism performed by the unfolded protein response (UPR) mediator Inositol Requiring Enzyme 1α (IRE1). Using Protein-RNA molecular docking along with a series of extensive restrained/unrestrained atomistic molecular dynamics (MD) simulations, the dynamical behavior of the system was evaluated and a reliable model of the IRE1/XBP1 mRNA complex was constructed. From a series of well-converged quantum mechanics molecular mechanics well-tempered metadynamics (QM/MM WT-MetaD) simulations using the Grimme dispersion interaction corrected semiempirical parametrization method 6 level of theory (PM6-D3) and the AMBER14SB-OL3 force field, the free energy profile of the cleavage mechanism was determined, along with intermediates and transition state structures. The results show two distinct reaction paths based on general acid-general base type mechanisms, with different activation energies that perfectly match observations from experimental mutagenesis data. The study brings unique atomistic insights into the cleavage mechanism of XBP1 mRNA by IRE1 and clarifies the roles of the catalytic residues H910 and Y892. Increased understanding of the details in UPR signaling can assist in the development of new therapeutic agents for its modulation.
    DOI:  https://doi.org/10.1021/acs.jcim.2c00735
  4. J Cell Physiol. 2022 Aug 12.
    The role of endoplasmic reticulum stress in the regulation of long noncoding RNAs in cancer.
    Nasim Ebrahimi, Jamileh Saremi, Masoud Ghanaatian, Elnaz Yazdani, Samaneh Adelian, Sahar Samsami, Neda Moradi, Nadi Rostami Ravari, Amirhossein Ahmadi, Michael R Hamblin, Amir Reza Aref.
      Cancer cells must overcome a variety of external and internal stresses to survive and proliferate. These unfavorable conditions include the accumulation of mutations, nutrient deficiency, oxidative stress, and hypoxia. These stresses can cause aggregation of misfolded proteins inside the endoplasmic reticulum. Under these conditions, the cell undergoes endoplasmic reticulum stress (ER-stress), and consequently initiates the unfolded protein response (UPR). Activation of the UPR triggers transcription factors and regulatory factors, including long noncoding RNAs (lncRNAs), which control the gene expression profile to maintain cellular stability and hemostasis. Recent investigations have shown that cancer cells can ensure their survival under adverse conditions by the UPR affecting the expression of lncRNAs. Therefore, understanding the relationship between lncRNA expression and ER stress could open new avenues, and suggest potential therapies to treat various types of cancer.
    Keywords:  ER stress; cell survival; long noncoding RNAs; signaling pathways; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1002/jcp.30846
  5. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041262. [Epub ahead of print]
    Evolutionary Aspects of the Unfolded Protein Response.
    Kazutoshi Mori.
      The unfolded protein response (UPR) is activated when unfolded proteins accumulate in the endoplasmic reticulum (ER). The basic mechanism of the UPR in maintaining ER homeostasis has been clarified from yeast to humans. The UPR is triggered by one or more transmembrane proteins in the ER. The number of canonical UPR sensors/transducers has increased during evolution, from one (IRE1) in yeast to three (IRE1, PERK, and ATF6) in invertebrates and five (IRE1α, IRE1β, PERK, ATF6α, and ATF6β) in vertebrates. Here, I initially describe the four major changes that have occurred during evolution: (1) advent of PERK in metazoans; (2) switch in transcription factor downstream of IRE1 in metazoans; (3) switch in regulator of ER chaperone induction in vertebrates; and (4) increase in the number of ATF6-like local factors in vertebrates. I then discuss the causes of the phenotypes of vertebrate knockout animals and refer to regulated IRE1-dependent decay of mRNAs.
    DOI:  https://doi.org/10.1101/cshperspect.a041262
  6. PLoS One. 2022 ;17(8): e0271695
    Newly synthesized mRNA escapes translational repression during the acute phase of the mammalian unfolded protein response.
    Mohammed R Alzahrani, Bo-Jhih Guan, Leah L Zagore, Jing Wu, Chien-Wen Chen, Donny D Licatalosi, Kristian E Baker, Maria Hatzoglou.
      Endoplasmic Reticulum (ER) stress, caused by the accumulation of misfolded proteins in the ER, elicits a homeostatic mechanism known as the Unfolded Protein Response (UPR). The UPR reprograms gene expression to promote adaptation to chronic ER stress. The UPR comprises an acute phase involving inhibition of bulk protein synthesis and a chronic phase of transcriptional induction coupled with the partial recovery of protein synthesis. However, the role of transcriptional regulation in the acute phase of the UPR is not well understood. Here we analyzed the fate of newly synthesized mRNA encoding the protective and homeostatic transcription factor X-box binding protein 1 (XBP1) during this acute phase. We have previously shown that global translational repression induced by the acute UPR was characterized by decreased translation and increased stability of XBP1 mRNA. We demonstrate here that this stabilization is independent of new transcription. In contrast, we show XBP1 mRNA newly synthesized during the acute phase accumulates with long poly(A) tails and escapes translational repression. Inhibition of newly synthesized RNA polyadenylation during the acute phase decreased cell survival with no effect in unstressed cells. Furthermore, during the chronic phase of the UPR, levels of XBP1 mRNA with long poly(A) tails decreased in a manner consistent with co-translational deadenylation. Finally, additional pro-survival, transcriptionally-induced mRNAs show similar regulation, supporting the broad significance of the pre-steady state UPR in translational control during ER stress. We conclude that the biphasic regulation of poly(A) tail length during the UPR represents a previously unrecognized pro-survival mechanism of mammalian gene regulation.
    DOI:  https://doi.org/10.1371/journal.pone.0271695
  7. Cell Mol Life Sci. 2022 Aug 06. 79(9): 472
    Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma.
    Mankun Wei, Uli Nurjanah, Arin Herkilini, Can Huang, Yanjun Li, Makoto Miyagishi, Shourong Wu, Vivi Kasim.
      Cholesterol biosynthesis plays a critical role in rapidly proliferating tumor cells. X-box binding protein 1 (XBP1), which was first characterized as a basic leucine zipper-type transcription factor, exists in an unspliced (XBP1-u) and spliced (XBP1-s) form. Recent studies showed that unspliced XBP1 (XBP1-u) has unique biological functions independent from XBP1-s and could promote tumorigenesis; however, whether it is involved in tumor metabolic reprogramming remains unknown. Herein, we found that XBP1-u promotes tumor growth by enhancing cholesterol biosynthesis in hepatocellular carcinoma (HCC) cells. Specifically, XBP1-u colocalizes with sterol regulatory element-binding protein 2 (SREBP2) and inhibits its ubiquitination/proteasomal degradation. The ensuing stabilization of SREBP2 activates the transcription of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. We subsequently show that the XBP1-u/SREBP2/HMGCR axis is crucial for enhancing cholesterol biosynthesis and lipid accumulation as well as tumorigenesis in HCC cells. Taken together, these findings reveal a novel function of XBP1-u in promoting tumorigenesis through increased cholesterol biosynthesis in hepatocarcinoma cells. Hence, XBP1-u might be a potential target for anti-tumor therapeutic strategies that focus on cholesterol metabolism in HCC.
    Keywords:  Cholesterol biosynthesis; SREBP2; Tumorigenesis; Unspliced XBP1 (XBP1-u); XBP1
    DOI:  https://doi.org/10.1007/s00018-022-04504-x
  8. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041261. [Epub ahead of print]
    Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
    Ana Paula Arruda, Güneş Parlakgül.
      The endoplasmic reticulum (ER) is a key organelle involved in the regulation of lipid and glucose metabolism, proteostasis, Ca2+ signaling, and detoxification. The structural organization of the ER is very dynamic and complex, with distinct subdomains such as the nuclear envelope and the peripheral ER organized into ER sheets and tubules. ER also forms physical contact sites with all other cellular organelles and with the plasma membrane. Both form and function of the ER are highly adaptive, with a potent capacity to respond to transient changes in environmental cues such as nutritional fluctuations. However, under obesity-induced chronic stress, the ER fails to adapt, leading to ER dysfunction and the development of metabolic pathologies such as insulin resistance and fatty liver disease. Here, we discuss how the remodeling of ER structure and contact sites with other organelles results in diversification of metabolic function and how perturbations to this structural flexibility by chronic overnutrition contribute to ER dysfunction and metabolic pathologies in obesity.
    DOI:  https://doi.org/10.1101/cshperspect.a041261
  9. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041266. [Epub ahead of print]
    Regulation and Functions of the ER-Associated Nrf1 Transcription Factor.
    Gary Ruvkun, Nicolas Lehrbach.
      Nrf1 is a member of the nuclear erythroid 2-like family of transcription factors that regulate stress-responsive gene expression in animals. Newly synthesized Nrf1 is targeted to the endoplasmic reticulum (ER) where it is N-glycosylated. N-glycosylated Nrf1 is trafficked to the cytosol by the ER-associated degradation (ERAD) machinery and is subject to rapid proteasomal degradation. When proteasome function is impaired, Nrf1 escapes degradation and undergoes proteolytic cleavage and deglycosylation. Deglycosylation results in deamidation of N-glycosylated asparagine residues to edit the protein sequence encoded by the genome. This truncated and "sequence-edited" form of Nrf1 enters the nucleus where it induces up-regulation of proteasome subunit genes. Thus, Nrf1 drives compensatory proteasome biogenesis in cells exposed to proteasome inhibitor drugs and other proteotoxic insults. In addition to its role in proteasome homeostasis, Nrf1 is implicated in responses to oxidative stress, and maintaining lipid and cholesterol homeostasis. Here, we describe the conserved and complex mechanism by which Nrf1 is regulated and highlight emerging evidence linking this unusual transcription factor to development, aging, and disease.
    DOI:  https://doi.org/10.1101/cshperspect.a041266
  10. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041248. [Epub ahead of print]
    The Role of the Rhomboid Superfamily in ER Protein Quality Control: From Mechanisms and Functions to Diseases.
    Satarupa Bhaduri, Nicola A Scott, Sonya E Neal.
      The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells and is a major site for protein folding, modification, and lipid synthesis. Perturbations within the ER, such as protein misfolding and high demand for protein folding, lead to dysregulation of the ER protein quality control network and ER stress. Recently, the rhomboid superfamily has emerged as a critical player in ER protein quality control because it has diverse cellular functions, including ER-associated degradation (ERAD), endosome Golgi-associated degradation (EGAD), and ER preemptive quality control (ERpQC). This breadth of function both illustrates the importance of the rhomboid superfamily in health and diseases and emphasizes the necessity of understanding their mechanisms of action. Because dysregulation of rhomboid proteins has been implicated in various diseases, such as neurological disorders and cancers, they represent promising potential therapeutic drug targets. This review provides a comprehensive account of the various roles of rhomboid proteins in the context of ER protein quality control and discusses their significance in health and disease.
    DOI:  https://doi.org/10.1101/cshperspect.a041248
  11. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041256. [Epub ahead of print]
    ER-Phagy: Quality and Quantity Control of the Endoplasmic Reticulum by Autophagy.
    Haruka Chino, Noboru Mizushima.
      The endoplasmic reticulum (ER) is the largest organelle and has multiple roles in various cellular processes such as protein secretion, lipid synthesis, calcium storage, and organelle biogenesis. The quantity and quality of this organelle are controlled by the ubiquitin-proteasome system and autophagy (termed "ER-phagy"). ER-phagy is defined as the degradation of part of the ER by the vacuole or lysosomes, and there are at least two types of ER-phagy: macro-ER-phagy and micro-ER-phagy. In macro-ER-phagy, ER fragments are enclosed by autophagosomes, which is mediated by ER-phagy receptors. In micro-ER-phagy, a portion of the ER is engulfed directly by the vacuole or lysosomes. In these two pathways, some proteins in the ER lumen can be recognized selectively and subjected to ER-phagy. This review summarizes our current knowledge of ER-phagy, focusing on its membrane dynamics, molecular mechanisms, substrate specificity, and physiological significance.
    DOI:  https://doi.org/10.1101/cshperspect.a041256
  12. iScience. 2022 Aug 19. 25(8): 104754
    The endoplasmic reticulum membrane complex promotes proteostasis of GABAA receptors.
    Angela L Whittsette, Ya-Juan Wang, Ting-Wei Mu.
      The endoplasmic reticulum membrane complex (EMC) plays a critical role in the biogenesis of tail-anchored proteins and a subset of multi-pass membrane proteins in the endoplasmic reticulum (ER). However, because of nearly exclusive expression of neurotransmitter-gated ion channels in the central nervous system (CNS), the role of the EMC in their biogenesis is not well understood. In this study, we demonstrated that the EMC positively regulates the surface trafficking and thus function of endogenous γ-aminobutyric acid type A (GABAA) receptors, the primary inhibitory ion channels in the mammalian brain. Moreover, among ten EMC subunits, EMC3 and EMC6 have the most prominent effect, and overexpression of EMC3 or EMC6 is sufficient to restore the function of epilepsy-associated GABAA receptor variants. In addition, EMC3 and EMC6 demonstrate endogenous interactions with major neuroreceptors, which depends on their transmembrane domains, suggesting a general role of the EMC in the biogenesis of neuroreceptors.
    Keywords:  Biological sciences; Cell biology; Molecular biology; Molecular neuroscience; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104754
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