bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022‒12‒04
six papers selected by
Susan Logue
University of Manitoba
  1. Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.
  2. miR-4734 conditionally suppresses ER stress-associated proinflammatory responses.
  3. Loss-of-rescue of Ryr1I4895T-related pathology by the genetic inhibition of the ER stress response mediator CHOP.
  4. A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b.
  5. ATF5 is a regulator of ER stress and β-cell apoptosis in different mouse models of genetic- and diet-induced obesity and diabetes mellitus.
  6. Non-alcoholic fatty liver disease and liver secretome.
  1. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01617-5. [Epub ahead of print]41(9): 111739
    Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.
    Reut Dudkevich, Jhee Hong Koh, Caroline Beaudoin-Chabot, Cenk Celik, Ilana Lebenthal-Loinger, Sarit Karako-Lampert, Syed Ahmad-Albukhari, Guillaume Thibault, Sivan Henis-Korenblit.
      Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.
    Keywords:  C. elegans; CP: Metabolism; IRE-1; IRE1; JNK; cell non-autonomous stress response; cold stress; endoplasmic reticulum; fat metabolism; lipids; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111739
  2. FEBS Lett. 2022 Nov 29.
    miR-4734 conditionally suppresses ER stress-associated proinflammatory responses.
    Dan Michael, Ester Feldmesser, Chagay Gonen, Noa Furth, Alexander Maman, Ori Heyman, Amir Argoetti, Adin Tofield, Amichai Baichman-Kass, Aviyah Ben-Dov, Dan Benbenisti, Nadav Hen, Ron Rotkopf, Federica Ganci, Giovanni Blandino, Igor Ulitsky, Moshe Oren.
      Prolonged metabolic stress can lead to severe pathologies. In metabolically challenged primary fibroblasts, we assigned a novel role for the poorly characterized miR-4734 in restricting ATF4 and IRE1-mediated upregulation of a set of proinflammatory cytokines and endoplasmic reticulum (ER) stress-associated genes. Conversely, inhibition of this miRNA augmented the expression of those genes. Mechanistically, miR-4734 was found to restrict the expression of the transcriptional activator NF-kappa-B inhibitor zeta (NFKBIZ), which is required for optimal expression of the proinflammatory genes and whose mRNA is targeted directly by miR-4734. Concordantly, overexpression of NFKBIZ compromised the effects of miR-4734, underscoring the importance of this direct targeting. As the effects of miR-4734 were evident under stress but not under basal conditions, it may possess therapeutic utility towards alleviating stress-induced pathologies.
    Keywords:  ATF4; ER stress; IRE1a; Inflammation; NFKBIZ; miR-4734
    DOI:  https://doi.org/10.1002/1873-3468.14548
  3. Sci Rep. 2022 Nov 30. 12(1): 20632
    Loss-of-rescue of Ryr1I4895T-related pathology by the genetic inhibition of the ER stress response mediator CHOP.
    Serena Germani, Alessia Celeste Marchetti, Andrea Guidarelli, Orazio Cantoni, Vincenzo Sorrentino, Ester Zito.
      RYR1 is the gene encoding the ryanodine receptor 1, a calcium release channel of the endo/sarcoplasmic reticulum. I4898T in RYR1 is one of the most common mutations that give rise to central core disease (CCD), with a variable phenotype ranging from mild to severe myopathy to lethal early-onset core-rod myopathy. Mice with the corresponding I4895T mutation in Ryr1 present mild myopathy when the mutation is heterozygous while I4895T homozygous is perinatal-lethal. Here we show that skeletal muscles of I4895T homozygous mice at birth present signs of stress of the endoplasmic reticulum (ER stress) and of the related unfolded protein response (UPR) with increased levels of the maladaptive mediators CHOP and ERO1. To gain information on the role of CHOP in the pathogenesis of RYR1I4895T-related myopathy, we generated compound Ryr1I4895T, Chop knock-out (-/-) mice. However, the genetic deletion of Chop, although it attenuates ER stress in the skeletal muscle of the newborns, does not rescue any phenotypic or functional features of Ryr1I4895T in mice: neither the perinatal-lethal phenotype nor the inability of Ryr1I4895T to respond to its agonist caffeine, but protects from ER stress-induced apoptosis. These findings suggest that genetic deletion of the ER stress response mediator CHOP is not sufficient to counteract the pathological Ryr1I4895T phenotype.
    DOI:  https://doi.org/10.1038/s41598-022-25198-y
  4. Elife. 2022 Nov 29. pii: e74805. [Epub ahead of print]11
    A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b.
    Shunsuke Saito, Tokiro Ishikawa, Satoshi Ninagawa, Tetsuya Okada, Kazutoshi Mori.
      A causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein that spans the ER membrane twice. Gain-of-function mutations of Seipin produce non-glycosylated Seipin (ngSeipin), which was previously shown to induce ER stress and apoptosis at both cell and mouse levels albeit with no clarified mechanism. We found that aggregation-prone ngSeipin dominantly inactivated SERCA2b, the major calcium pump in the ER, and decreased the calcium concentration in the ER, leading to ER stress and apoptosis in human colorectal carcinoma-derived cells (HCT116). This inactivation required oligomerization of ngSeipin and direct interaction of the C-terminus of ngSeipin with SERCA2b, and was observed in Seipin-deficient neuroblastoma (SH-SY5Y) cells expressing ngSeipin at an endogenous protein level. Our results thus provide a new direction to the controversy noted above.
    Keywords:  ER stress; UPR; apoptosis; calcium pump; cell biology; human; neurodegenerative disease
    DOI:  https://doi.org/10.7554/eLife.74805
  5. Cell Signal. 2022 Nov 24. pii: S0898-6568(22)00297-2. [Epub ahead of print] 110535
    ATF5 is a regulator of ER stress and β-cell apoptosis in different mouse models of genetic- and diet-induced obesity and diabetes mellitus.
    Jinfang Ma, Yuqi Liu, Ismael Valladolid Acebes, Patricia Recio López, Ge Peng, Juan Li, Per-Olof Berggren, Lisa Juntti-Berggren, Nanwei Tong.
      Endoplasmic reticulum (ER) stress is closely associated with type 2 diabetes (T2D). Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element binding protein (CREB) family whose levels are increased upon stress in pancreatic islets from mice. Intriguingly, ATF5 deficiency has been shown to contribute to increased ER stress and apoptosis in mouse islet micro-organs. We hypothesized that either deficiency or overexpression of ATF5 is equally deleterious for pancreatic islets in terms of ER stress and apoptosis. To test this, we used a number of in vitro and in vivo models whereby ATF5 levels were overexpressed. We also determined the regulation of ATF5 in the context of metabolic derangements by using various mouse models of obesity and T2D. Our in vitro results show that ATF5 overexpression promoted palmitic acid (PA)-induced lipotoxic apoptosis. In vivo, global ATF5 overexpression in mice was lethal and pancreas-specific ATF5 overexpressing mice exhibit increased β-cell apoptosis. Interestingly, ATF5 is downregulated in all mouse models of severe obesity and T2D used in the current study. In conclusion, a tight control on ATF5 levels might be considered when developing novel agents targeting ATF5 for prevention and treatment of metabolic diseases.
    Keywords:  Activated transcription factor 5; Endoplasmic reticulum stress; Inflammation; Islet beta cells; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110535
  6. Arch Pharm Res. 2022 Nov 28.
    Non-alcoholic fatty liver disease and liver secretome.
    Muhammad Sohaib Khan, Choongho Lee, Sang Geon Kim.
      Metabolism of carbohydrates and lipids and protein degradation occurs in the liver and contributes to the body's homeostasis by secreting a variety of mediators. Any imbalance in this homeostasis due to excess fat consumption and the pathologic events accompanying lipotoxicity, autophagy dysregulation, endoplasmic reticulum stress, and insulin resistance may cause disturbances in the secretion of the proteins from the liver and their physiologic modifications and interactions with others. Since the liver secretome plays a role in the regulation of fuel metabolism and inflammation not only in the liver per se but also in other organs, the proteins belong to the utmost targets for treating metabolic and inflammatory diseases (e.g., COVID-19), depending on the available and feasible approaches to controlling their biological effects. However, in this era, we still come across new liver-derived proteins but are yet unable to entirely understand the pathologic basis underlying disease progression. This review aims to provide an updated overview of liver secretome biology with explanatory mechanisms with regard to the progression of metabolic and inflammatory liver diseases.
    Keywords:  Autophagy; COVID-19; ER stress; Hepatokines; Liver disorders
    DOI:  https://doi.org/10.1007/s12272-022-01419-w
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