bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–08–07
six papers selected by
Susan Logue, University of Manitoba
  1. Role of Long Non-Coding RNA in Regulating ER Stress Response on the Progression of Diabetic Complications.
  2. Cell death induction in Aspergillus fumigatus: accentuating drug toxicity through inhibition of the unfolded protein response (UPR).
  3. PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells.
  4. Ca2+ signalling system initiated by endoplasmic reticulum stress stimulates PERK activation.
  5. The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases.
  6. Identification of an ERN1 target site within EGFP mRNA.
  1. Curr Gene Ther. 2022 Aug 01.
    Role of Long Non-Coding RNA in Regulating ER Stress Response on the Progression of Diabetic Complications.
    Ramanarayanan Vijayalalitha, Architha Tca, George Raj Juanitaa, Ravichandran Jayasuriya, Karan Naresh Amin, Kunka Mohanram Ramkumar.
      Chronic hyperglycemia damages the nerves, blood vessels, culminating in other vascular complications. Such complications enhance cytokine, oxidative and endoplasmic reticulum (ER) stress. ER is the primary organelle where proteins are synthesised and attains confirmatory changes before its site of destination. Perturbation of ER homeostasis activates signaling sensors within its lumen, the unfolded protein response (UPR) that orchestrates ER stress and is extensively studied. Increased ER stress markers are reported in diabetic complications in addition to lncRNA that acts as an upstream marker inducing ER stress response. This review focuses on the mechanisms of lncRNA that regulate ER stress markers, especially during the progression of diabetic complications. Through this systemic review, we showcase the dysfunctional lncRNAs that acts as a leading cause of ER stress response on the progression of diabetic complications.
    Keywords:  ER stress; diabetic complications; lncRNA
    DOI:  https://doi.org/10.2174/1566523222666220801141450
  2. Curr Res Microb Sci. 2022 ;3 100119
    Cell death induction in Aspergillus fumigatus: accentuating drug toxicity through inhibition of the unfolded protein response (UPR).
    José P Guirao-Abad, Martin Weichert, David S Askew.
      One of the most potent opportunistic fungal pathogens of humans is Aspergillus fumigatus, an environmental mold that causes a life-threatening pneumonia with a high rate of morbidity and mortality. Despite advances in therapy, issues of drug toxicity and antifungal resistance remain an obstacle to effective therapy. This underscores the need for more information on fungal pathways that could be pharmacologically manipulated to either reduce the viability of the fungus during infection, or to unleash the fungicidal potential of current antifungal drugs. In this review, we summarize the emerging evidence that the ability of A. fumigatus to sustain viability during stress relies heavily on an adaptive signaling pathway known as the unfolded protein response (UPR), thereby exposing a vulnerability in this fungus that has strong potential for future therapeutic intervention.
    Keywords:  Aspergillus fumigatus; ER stress; HacA; IreA; UPR; cell death
    DOI:  https://doi.org/10.1016/j.crmicr.2022.100119
  3. Sci Rep. 2022 Aug 03. 12(1): 13324
    PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells.
    Neil Saptarshi, Louise F Porter, Luminita Paraoan.
      Retinal pigment epithelium (RPE) performs essential functions for ensuring retinal homeostasis and is a key site for pathogenic changes leading to age-related macular degeneration (AMD). Compromised proteostasis in RPE results in ER stress and ER stress-dependent antioxidant, apoptosis and autophagic responses. ER stress induces the unfolded protein response (UPR) in which EIF2AK3, encoding the protein kinase RNA-like ER kinase (PERK), acts as a key regulator. Downregulated EIF2AK3 gene expression has recently been identified in AMD using human donor RPE, however the molecular mechanisms that integrate the various ER-mediated cellular pathways underpinning progressive RPE dysfunction in AMD have not been fully characterised. This study investigated the downstream effects of PERK downregulation in response to Brefeldin A (BFA)-induced ER stress in ARPE-19 cells. PERK downregulation resulted in increased ER stress and impaired apoptosis induction, antioxidant responses and autophagic flux. ARPE-19 cells were unable to efficiently induce autophagy following PERK downregulation and PERK presented a role in regulating the rate of autophagy induction. The findings support PERK downregulation as an integrative event facilitating dysregulation of RPE processes critical to cell survival known to contribute to AMD development and highlight PERK as a potential future therapeutic target for AMD.
    DOI:  https://doi.org/10.1038/s41598-022-16909-6
  4. Cell Calcium. 2022 Jul 20. pii: S0143-4160(22)00095-1. [Epub ahead of print]106 102622
    Ca2+ signalling system initiated by endoplasmic reticulum stress stimulates PERK activation.
    Constanza Feliziani, Macarena Fernandez, Gonzalo Quassollo, Deborah Holstein, Sebastián M Bairo, James C Paton, Adrienne W Paton, Juan de Batista, James D Lechleiter, Mariana Bollo.
      The accumulation of unfolded proteins within the Endoplasmic Reticulum (ER) activates a signal transduction pathway termed the unfolded protein response (UPR), which attempts to restore ER homoeostasis. If this cannot be done, UPR signalling ultimately induces apoptosis. Ca2+ depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca2+ as an intracellular messenger, the precise mechanism(s) by which Ca2+ release affects the UPR remains unknown. Tethering a genetically encoded Ca2+ indicator (GCamP6) to the ER membrane revealed novel Ca2+ signalling events initiated by Ca2+ microdomains in human astrocytes under ER stress, induced by tunicamycin (Tm), an N-glycosylation inhibitor, as well as in a cell model deficient in all three inositol triphosphate receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons and that the Ca2+ microdomains impact (PKR)-like-ER kinase (PERK), an UPR sensor, activation. These findings reveal the existence of a Ca2+ signal mechanism by which stressor-mediated Ca2+ release regulates ER stress.
    Keywords:  (PKR)-like-ER kinase (PERK); Calcium signalling; Inositol triphosphate receptor; Translocon; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.ceca.2022.102622
  5. Ageing Res Rev. 2022 Jul 28. pii: S1568-1637(22)00144-1. [Epub ahead of print]81 101702
    The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases.
    Zixin Zhou, Yumei Fan, Ruikai Zong, Ke Tan.
      Mitochondria, which serve as the energy factories of cells, are involved in cell differentiation, calcium homeostasis, amino acid and fatty acid metabolism and apoptosis. In response to environmental stresses, mitochondrial homeostasis is regulated at both the organelle and molecular levels to effectively maintain the number and function of mitochondria. The mitochondrial unfolded protein response (UPRmt) is an adaptive intracellular stress mechanism that responds to stress signals by promoting the transcription of genes encoding mitochondrial chaperones and proteases. The mechanism of the UPRmt in Caenorhabditis elegans (C. elegans) has been clarified over time, and the main regulatory factors include ATFS-1, UBL-5 and DVE-1. In mammals, the activation of the UPRmt involves eIF2α phosphorylation and the uORF-regulated expression of CHOP, ATF4 and ATF5. Several additional factors, such as SIRT3 and HSF1, are also involved in regulating the UPRmt. A deep and comprehensive exploration of the UPRmt can provide new directions and strategies for the treatment of human diseases, including aging, neurodegenerative diseases, cardiovascular diseases and diabetes. In this review, we mainly discuss the function of UPRmt, describe the regulatory mechanisms of UPRmt in C. elegans and mammals, and summarize the relationship between UPRmt and various human diseases.
    Keywords:  ATFS-1; Aging; Mitochondria stress; Mitochondrial unfolded protein response; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.arr.2022.101702
  6. J Cell Biochem. 2022 Jul 31.
    Identification of an ERN1 target site within EGFP mRNA.
    Marius W Baeken, Yohei Yokobayashi.
      EGFP (enhanced green fluorescent protein) is one of the most common tools used in life sciences, including research focusing on proteostasis. Here we report that ERN1 (endoplasmic reticulum to nucleus signaling 1), which is upregulated by UPR (unfolded protein response), targets an RNA hairpin loop motif in EGFP mRNA. A silent mutation introduced into EGFP mRNA abolished the ERN1-dependent mRNA decay. Therefore, experiments that employ EGFP as a reporter gene in studies that involve upregulation of the UPR pathway should be interpreted carefully, and a mutant devoid of the ERN1 target motif may be more suitable for such studies.
    Keywords:  EGFP; ERN1; IRE1; proteostasis; unfolded protein response
    DOI:  https://doi.org/10.1002/jcb.30314
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