bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024–11–17
eight papers selected by
Susan Logue, University of Manitoba
  1. Central role of the ER proteostasis network in healthy aging.
  2. Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy.
  3. The role of microRNAs regulation of endoplasmic reticulum stress in ischemia-reperfusion injury: A review.
  4. Discovery of a Compound That Inhibits IRE1α S-Nitrosylation and Preserves the Endoplasmic Reticulum Stress Response under Nitrosative Stress.
  5. Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.
  6. MIST1 regulates endoplasmic reticulum stress-induced hepatic apoptosis as a candidate marker of fatty liver disease progression.
  7. Regulation of chondrocyte apoptosis in osteoarthritis by endoplasmic reticulum stress.
  8. Metabolic RNA Labeling and Translating Ribosome Affinity Purification for Measurement of Nascent RNA Translation.
  1. Trends Cell Biol. 2024 Nov 14. pii: S0962-8924(24)00209-5. [Epub ahead of print]
    Central role of the ER proteostasis network in healthy aging.
    Claudio Hetz, Andrew Dillin.
      Aging trajectories vary among individuals, characterized by progressive functional decline, often leading to disease states. One of the central hallmarks of aging is the deterioration of proteostasis, where the function of the endoplasmic reticulum (ER) is dramatically affected. ER stress is monitored and adjusted by the unfolded protein response (UPR); a signaling pathway that mediates adaptive processes to restore proteostasis. Studies in multiple model organisms (yeast, worms, flies, and mice) in addition to human tissue indicates that adaptive UPR signaling contributes to healthy aging. Strategies to improve ER proteostasis using small molecules and gene therapy reduce the decline of organ function during normal aging in mammals. This article reviews recent advances in understanding the significance of the ER proteostasis network to normal aging and its relationship with other hallmarks of aging such as senescence.
    Keywords:  aging; endoplasmic reticulum stress; proteostasis; senescence; unfolded protein response
    DOI:  https://doi.org/10.1016/j.tcb.2024.10.003
  2. Metabolism. 2024 Nov 06. pii: S0026-0495(24)00290-7. [Epub ahead of print] 156062
    Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy.
    Irem Congur, Geltrude Mingrone, Kaomei Guan.
      Endoplasmic reticulum (ER) is an essential organelle involved in vesicular transport, calcium handling, protein synthesis and folding, and lipid biosynthesis and metabolism. ER stress occurs when ER homeostasis is disrupted by the accumulation of unfolded and/or misfolded proteins in the ER lumen. Adaptive pathways of the unfolded protein response (UPR) are activated to maintain ER homeostasis. In obesity and type 2 diabetes mellitus (T2DM), accumulating data indicate that persistent ER stress due to maladaptive UPR interacts with insulin/leptin signaling, which may be the potential and central mechanistic link between obesity-/T2DM-induced metabolic dysregulation (chronic hyperglycemia, dyslipidemia and lipotoxicity in cardiomyocytes), insulin/leptin resistance and the development of diabetic cardiomyopathy (DiabCM). Meanwhile, these pathological conditions further exacerbate ER stress. However, their interrelationships and the underlying molecular mechanisms are not fully understood. A deeper understanding of ER stress-mediated pathways in DiabCM is needed to develop novel therapeutic strategies. The aim of this review is to discuss the crosstalk between ER stress and leptin/insulin signaling and their involvement in the development of DiabCM focusing on mitochondria-associated ER membranes and chronic inflammation. We also present the current direction of drug development and important considerations for translational research into targeting ER stress for the treatment of DiabCM.
    Keywords:  Diabetic cardiomyopathy; ER stress; Insulin; Leptin; Lipotoxicity; Mitochondria-associated ER membrane
    DOI:  https://doi.org/10.1016/j.metabol.2024.156062
  3. Int J Biol Macromol. 2024 Nov 12. pii: S0141-8130(24)08376-4. [Epub ahead of print] 137566
    The role of microRNAs regulation of endoplasmic reticulum stress in ischemia-reperfusion injury: A review.
    Wanying Liu, Qi Zhang, Shiyun Guo, Honggang Wang.
      The endoplasmic reticulum (ER) is an important organelle in eukaryotic cells, responsible for a range of biological functions such as the secretion, modification and folding of proteins, maintaining Ca2+ homeostasis and the synthesis of steroids/lipids, secreted proteins and membrane proteins. When cells are affected by internal or external factors, including abnormal energy metabolism, disrupted Ca2+ balance, altered glycosylation, drug toxicity, and so on, the unfolded or misfolded proteins accumulate in the ER, leading to the unfolded protein response (UPR) and ER stress. The abnormal ER stress has been reported to be involved in various pathological processes. MicroRNAs (miRNAs) are non-coding RNAs with the length of approximately 19-25 nucleotides. They control the expression of multiple genes through posttranscriptional gene silencing in eukaryotes or some viruses. Increasing evidence indicates that miRNAs are involved in various cellular functions and biological processes, such as cell proliferation and differentiation, growth and development, and metabolic homeostasis. Hence, miRNAs participate in multiple pathological processes. Recently, many studies have shown that miRNAs play an important role by regulating ER stress in ischemia-reperfusion (I/R) injury, but the relevant mechanisms are not fully understood. In this review, we reviewed the current understanding of ER stress, as well as the biogenesis and function of miRNAs, and focused on the role of miRNAs regulation of ER stress in I/R injury, with the aim of providing new targets for the treatment of I/R injury.
    Keywords:  Endoplasmic reticulum stress; Gene silencing; Ischemia-reperfusion injury; MicroRNAs
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137566
  4. ACS Chem Biol. 2024 Nov 12.
    Discovery of a Compound That Inhibits IRE1α S-Nitrosylation and Preserves the Endoplasmic Reticulum Stress Response under Nitrosative Stress.
    Haruna Kurogi, Nobumasa Takasugi, Sho Kubota, Ashutosh Kumar, Takehiro Suzuki, Naoshi Dohmae, Daisuke Sawada, Kam Y J Zhang, Takashi Uehara.
      Inositol-requiring enzyme 1α (IRE1α) is a sensor of endoplasmic reticulum (ER) stress and drives ER stress response pathways. Activated IRE1α exhibits RNase activity and cleaves mRNA encoding X-box binding protein 1, a transcription factor that induces the expression of genes that maintain ER proteostasis for cell survival. Previously, we showed that IRE1α undergoes S-nitrosylation, a post-translational modification induced by nitric oxide (NO), resulting in reduced RNase activity. Therefore, S-nitrosylation of IRE1α compromises the response to ER stress, making cells more vulnerable. We conducted virtual screening and cell-based validation experiments to identify compounds that inhibit the S-nitrosylation of IRE1α by targeting nitrosylated cysteine residues. We ultimately identified a compound (1ACTA) that selectively inhibits the S-nitrosylation of IRE1α and prevents the NO-induced reduction of RNase activity. Furthermore, 1ACTA reduces the rate of NO-induced cell death. Our research identified S-nitrosylation as a novel target for drug development for IRE1α and provides a suitable screening strategy.
    DOI:  https://doi.org/10.1021/acschembio.4c00403
  5. Cell Rep. 2024 Nov 12. pii: S2211-1247(24)01323-8. [Epub ahead of print]43(11): 114972
    Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.
    Xu Han, Michelle Burrows, Laura C Kim, Jimmy P Xu, Will Vostrejs, Tran Ngoc Van Le, Carson Poltorack, Yanqing Jiang, Edna Cukierman, Ben Z Stanger, Kim A Reiss, Sydney M Shaffer, Clementina Mesaros, Brian Keith, M Celeste Simon.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with abundant cancer-associated fibroblasts (CAFs) creating hallmark desmoplasia that limits oxygen and nutrient delivery. This study explores the importance of lipid homeostasis under stress. Exogenous unsaturated lipids, rather than de novo synthesis, sustain PDAC cell viability by relieving endoplasmic reticulum (ER) stress under nutrient scarcity. Furthermore, CAFs are less hypoxic than adjacent malignant cells in vivo, nominating them as a potential source of unsaturated lipids. CAF-conditioned medium promotes PDAC cell survival upon nutrient and oxygen deprivation, an effect reversed by delipidation. Lysophosphatidylcholines (LPCs) are particularly enriched in CAF-conditioned medium and preferentially taken up by PDAC cells, where they are converted to phosphatidylcholine (PC) to sustain membrane integrity. Blocking LPC-to-PC conversion inhibits PDAC cell survival and increases ER stress. These findings show a critical lipid "cross-feeding" mechanism that promotes PDAC cell survival, offering a potential metabolic target for treatment.
    Keywords:  CP: Cancer; CP: Metabolism; fibroblasts; hypoxia; lipids; pancreatic cancer; tumor microenvironment; unsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.celrep.2024.114972
  6. Cell Death Dis. 2024 Nov 08. 15(11): 805
    MIST1 regulates endoplasmic reticulum stress-induced hepatic apoptosis as a candidate marker of fatty liver disease progression.
    Sumin Hur, Haengdueng Jeong, Keunyoung Kim, Kwang H Kim, Sung Hee Kim, Yura Lee, Ki Taek Nam.
      The liver regenerates after injury; however, prolonged injury can lead to chronic inflammation, fatty liver disease, fibrosis, and cancer. The mechanism involving the complex pathogenesis of the progression of liver injury to chronic liver disease remains unclear. In this study, we investigated the dynamics of gene expression associated with the progression of liver disease. We analyzed changes in gene expression over time in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis using high-throughput RNA sequencing. Prolonged CCl4-induced liver injury increased the expression levels of genes associated with the unfolded protein response (UPR), which correlated with the duration of injury, with substantial, progressive upregulation of muscle, intestine, and stomach expression 1 (Mist1, bhlha15) in the mouse fibrosis model and other liver-damaged tissues. Knockdown of MIST1 in HepG2 cells decreased tribbles pseudokinase 3 (TRIB3) levels and increased apoptosis, consistent with the patterns detected in Mist1-knockout mice. MIST1 expression was confirmed in liver tissues from patients with metabolic dysfunction-associated steatohepatitis and alcoholic steatohepatitis (MASH) and correlated with disease progression. In conclusion, MIST1 is expressed in hepatocytes in response to damage, suggesting a new indicator of liver disease progression. Our results suggest that MIST1 plays a key role in the regulation of apoptosis and TRIB3 expression contributing to progressive liver disease after injury.
    DOI:  https://doi.org/10.1038/s41419-024-07217-0
  7. Cell Stress Chaperones. 2024 Nov 06. pii: S1355-8145(24)00126-3. [Epub ahead of print]
    Regulation of chondrocyte apoptosis in osteoarthritis by endoplasmic reticulum stress.
    Renzhong Li, Kui Sun.
      Osteoarthritis(OA), a common degenerative joint disease, is characterized by the apoptosis of chondrocytes as a primary pathophysiological change, with endoplasmic reticulum stress(ERS) playing a crucial role. It has been demonstrated that an imbalance in endoplasmic reticulum(ER) homeostasis can lead to ERS, activating three cellular adaptive response pathways through the unfolded protein response(UPR) to restore ER homeostasis. Mild ERS exerts a protective effect on cells, while prolonged ERS that disrupts the self-regulatory balance of the endoplasmic reticulum activates apoptotic signaling pathways, leading to chondrocyte apoptosis and hastening OA progression. Hence, controlling the ERS signaling pathway and its apoptotic factors has become a critical focus for preventing and treating OA. This review aims to elucidate the key mechanisms of ERS pathway-induced apoptosis, associated targets, and regulatory pathways, offering valuable insights to enhance the mechanistic understanding of OA. And it also reviews the mechanisms studied for ERS-related drugs or compounds for the treatment of OA.
    Keywords:  Apoptosis; Endoplasmic Reticulum Stress; Osteoarthritis; Review; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cstres.2024.11.001
  8. Bio Protoc. 2024 Oct 20. 14(20): e5091
    Metabolic RNA Labeling and Translating Ribosome Affinity Purification for Measurement of Nascent RNA Translation.
    Hirotatsu Imai, Akio Yamashita.
      Regulation of gene expression in response to various biological processes, including extracellular stimulation and environmental adaptation, requires nascent mRNA synthesis and translation. Simultaneous analysis of the coordinated regulation of dynamic mRNA synthesis and translation using the same experiment remains a major challenge in the field. Here, we describe a step-by-step protocol for the simultaneous measurement of transcription of nascent mRNA and its translation at the gene level during the acute unfolded protein response (UPR) in HEK293 cells by combining 4-thiouridine metabolic mRNA labeling with translational ribosome affinity purification (TRAP) using a monoclonal antibody against evolutionarily conserved ribosomal P-stalk proteins (P-TRAP). Since P-TRAP captures full-length RNAs bound to ribosomes, it is compatible with 3' mRNA-seq, which analyzes the uridine-rich 3' UTRs of polyadenylated RNAs, allowing robust quantification of T>C conversions. Our nascent P-TRAP (nP-TRAP) method, in which P-TRAP is combined with metabolic mRNA labeling, can serve as a simple and powerful tool to analyze the coordinated regulation of transcription and translation of individual genes in cultured cells. Key features • Simple and retriable analysis of nascent mRNA synthesis and its translation in cultured cells • Combination of 4-thiouridine metabolic RNA labeling with translating ribosome affinity purification (TRAP) • Ribosomal P-stalk-mediated TRAP (P-TRAP) allows single-step and efficient purification of non-tagged ribosomes and translated mRNAs.
    Keywords:  4-thiouridine; Deep sequencing; Metabolic RNA labeling; TRAP-seq; Transcription; Translating ribosome affinity purification; Translation
    DOI:  https://doi.org/10.21769/BioProtoc.5091
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