bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒07‒26
nine papers selected by
Susan Logue
University of Manitoba


  1. Nat Chem Biol. 2020 Jul 20.
    Grandjean JMD, Madhavan A, Cech L, Seguinot BO, Paxman RJ, Smith E, Scampavia L, Powers ET, Cooley CB, Plate L, Spicer TP, Kelly JW, Wiseman RL.
      Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly selective IRE1/XBP1s activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
    DOI:  https://doi.org/10.1038/s41589-020-0584-z
  2. Biomolecules. 2020 Jul 22. pii: E1090. [Epub ahead of print]10(8):
    van Ziel AM, Scheper W.
      Neurons are highly specialized cells that continuously and extensively communicate with other neurons, as well as glia cells. During their long lifetime, the post-mitotic neurons encounter many stressful situations that can disrupt protein homeostasis (proteostasis). The importance of tight protein quality control is illustrated by neurodegenerative disorders where disturbed neuronal proteostasis causes neuronal dysfunction and loss. For their unique function, neurons require regulated and long-distance transport of membrane-bound cargo and organelles. This highlights the importance of protein quality control in the neuronal endomembrane system, to which the unfolded protein response (UPR) is instrumental. The UPR is a highly conserved stress response that is present in all eukaryotes. However, recent studies demonstrate the existence of cell-type-specific aspects of the UPR, as well as cell non-autonomous UPR signaling. Here we discuss these novel insights in view of the complex cellular architecture of the brain and the implications for neurodegenerative diseases.
    Keywords:  cell non-autonomous; neurodegenerative disease; proteostasis; unconventional secretion; unfolded protein response
    DOI:  https://doi.org/10.3390/biom10081090
  3. Biochem Biophys Res Commun. 2020 Aug 20. pii: S0006-291X(20)31243-2. [Epub ahead of print]529(2): 335-340
    Xiong Y, Wang Y, Xiong Y, Gao W, Teng L.
      Endoplasmic reticulum (ER) stress and subsequent apoptosis played vital role in liver injury and dysfunction. The aim of this study was to investigate the protective effect and mechanism of salidroside on hypoxia induced liver injury both in vivo and in vitro. Male SD rats were exposed to hypobaric chamber to simulate high altitude hypoxia model. High altitude hypoxia led to significant liver injury and apoptosis, increased the expression levels of p-JNK, BAX and ER stress markers. Salidroside treatment significantly inhibited hypoxia induced ER stress by decreasing the protein expression of glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated inositol-requiring enzyme 1α (p-IRE1α). In addition, salidroside treatment also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins p-JNK, TRAF2, BAX, and cleaved caspase 9 and caspase 12, as well as upregulation of Bcl-2. Furthermore, in vitro study found that blocking IRE1α pathway using specific inhibitor STF-083010 subsequently reversed the protective effect of salidroside on liver apoptosis. Taken together, our findings revealed that salidroside exerts protective effects against hypoxia induced liver injury through inhibiting ER stress mediated apoptosis via IRE1α/JNK pathway.
    Keywords:  Apoptosis; Endoplasmic reticulum stress; Hypoxia; IRE1α; Salidroside
    DOI:  https://doi.org/10.1016/j.bbrc.2020.06.036
  4. J Biol Chem. 2020 Jul 20. pii: jbc.RA120.012849. [Epub ahead of print]
    Yao X, Li K, Liang C, Zhou Z, Wang J, Wang S, Liu L, Yu CL, Song ZB, Bao YL, Zheng LH, Sun Y, Wang G, Huang Y, Yi J, Sun L, Li Y.
      Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet β-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to β-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve β-cell mass and function. Previously, we established a PDX1 promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for PDX1 gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in β-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of β-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. These effects held true in vivo as well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet β-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring β-cell mass and islet size respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD impaired glucose metabolism in mice, as evidenced by ameliorating hyperglycemia and glucose intolerance. Taken together, TG, as an agent promoting PDX1 expression exhibits strong protective effects on islet β-cells both in vitro and in vivo.
    Keywords:  Type 2 diabetes; apoptosis; drug discovery; endoplasmic reticulum stress (ER stress); glucotoxicity; lipotoxicity; pancreatic islet
    DOI:  https://doi.org/10.1074/jbc.RA120.012849
  5. Mol Cell Endocrinol. 2020 Jul 18. pii: S0303-7207(20)30248-3. [Epub ahead of print] 110948
    Soczewski E, Gori S, Paparini D, Grasso E, Fernández L, Gallino L, Schafir A, Irigoyen M, Lobo TF, Salamone G, Mattar R, Daher S, Leirós CP, Ramhorst R.
      Endometrial stromal cells undergo endoplasmic reticulum (ER) stress and unfolded protein response (UPR) during the decidualization linked with the inflammation and angiogenesis processes. Considering VIP (vasoactive intestinal peptide) induces the decidualization program, we studied whether modulates the ER/UPR pathways to condition both processes for embryo implantation. When Human endometrial stromal cell line (HESC) were decidualized by VIP we observed an increase expression of ATF6α, an ER stress-sensor, and UPR markers, associated with an increase in IL-1β production. Moreover, AEBSF (ATF6α -inhibitor pathway) prevented this effect and decreased the expansion index in the in vitro model of implantation. VIP-decidualized cells also favor angiogenesis accompanied by a strong downregulation in thrombospondin-1. Finally, ATF6α, VIP and VPAC2-receptor expression were reduced in endometrial biopsies from women with recurrent implantation failures in comparison with fertile. In conclusion, VIP privileged ATF6α-pathway associated with a sterile inflammatory response and angiogenesis that might condition endometrial receptivity.
    Keywords:  Decidualization; Reticular stress; Sterile inflammation; Unfolded protein response; Vasoactive intestinal peptide
    DOI:  https://doi.org/10.1016/j.mce.2020.110948
  6. Biochim Biophys Acta Mol Basis Dis. 2020 Jul 19. pii: S0925-4439(20)30247-7. [Epub ahead of print] 165899
    Chen Q, Samidurai A, Thompson J, Hu Y, Das A, Willard B, Lesnefsky EJ.
      Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 mo. mice that manifest mitochondrial dysfunction. OXPHOS was decreased in 24 mo. IFM oxidizing complex I and complex IV substrates. Proteomic analysis showed that the content of multiple complex I subunits was decreased in IFM from 24 mo. hearts, but remained unchanged in in 18 mo. IFM without a decrease in OXPHOS. Feeding 24 mo. old mice with 4-phenylbutyrate (4-PBA) for two weeks attenuated the ER stress and improved mitochondrial function. These results indicate that ER stress contributes to the mitochondrial dysfunction in aged hearts. Attenuation of ER stress is a potential approach to improve mitochondrial function in aged hearts.
    Keywords:  4-Phenylbutyrate; Aging; Complex I; Electron transport chain
    DOI:  https://doi.org/10.1016/j.bbadis.2020.165899
  7. Biochem Biophys Res Commun. 2020 Aug 20. pii: S0006-291X(20)31273-0. [Epub ahead of print]529(2): 480-486
    Yue XY, Sun XF, Che K, Hu JX, Lv WS, Sun XL, Geng Z, Chi JW, Wang YG.
      Primary Hypertriglyceridemia refers to a loss-of-function genetic defect which prevents the triglyceride (TG) in chylomicrons (CM) from lipolysis, leading to the accumulation of TG. The mutation of lipoprotein lipase (LPL) gene has been recognized as the main cause of primary hypertriglyceridemia. Recently, a new LPL gene mutation p.C310R(c. T928C) was identified in a family with hypertriglyceridemia. The proband was manifested by severe hypertriglyceridemia and diabetes. Skeletal muscle is the major LPL-synthesizing tissue and insulin response target tissue. However, little is known about the effects of LPL gene mutation on skeletal muscle. This study is intended to observe the effects of LPL-C310R mutation on glycolipid metabolism and skeletal muscle. We found that a significantly decreased LPL plasma concentration, activity and the expression levels in skeletal muscle were observed in LplC310R/+ mice comparing to wild type mice. Those mutant mice also exhibited increased fasting plasma TG, free fat acids (FFA) and insulin, as well as FFA in muscle, and decreased glucose tolerance. Enhanced expression of BIP and elevated phosphorylation of IRE1α were observed in skeletal muscle, suggesting increased endoplasmic reticulum stress (ERS). Consistent with this, increased phosphorylation of JNK was also observed. Meanwhile, remarkably enhanced phosphorylation of IRS-1 (Ser307) and decreased phosphorylation of AKT were observed in skeletal muscle of mutant mice, suggesting impaired insulin signaling. Significant lipid deposition and morphological changes in endoplasmic reticulum and mitochondria were observed in the skeletal muscle of mutant mice but not in wild type control. Results demonstrate Lpl C310R mutation caused impaired glucose tolerance, ER stress and impaired insulin signaling in skeletal muscle.
    Keywords:  Endoplasmic reticulum stress; Hypertriglyceridemia; Lipoprotein lipase; Mutation; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.bbrc.2020.06.055
  8. J Immunol. 2020 Jul 22. pii: ji2000132. [Epub ahead of print]
    Hosaka Y, Araya J, Fujita Y, Kadota T, Tsubouchi K, Yoshida M, Minagawa S, Hara H, Kawamoto H, Watanabe N, Ito A, Ichikawa A, Saito N, Okuda K, Watanabe J, Takekoshi D, Utsumi H, Hashimoto M, Wakui H, Ito S, Numata T, Mori S, Matsudaira H, Hirano J, Ohtsuka T, Nakayama K, Kuwano K.
      Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells.
    DOI:  https://doi.org/10.4049/jimmunol.2000132
  9. Transl Oncol. 2020 Jul 17. pii: S1936-5233(20)30326-0. [Epub ahead of print]13(11): 100834
    Liu Y, Awadia S, Delaney A, Sitto M, Engelke C, Patel H, Calcaterra A, Zelenka-Wang S, Lee H, Contessa J, Neamati N, Ljungman M, Lawrence TS, Morgan MA, Rehemtulla A.
      The Unfolded Protein Response (UPR) plays a key role in the adaptive response to loss of protein homeostasis within the endoplasmic reticulum (ER). The UPR has an adaptive function in protein homeostasis, however, sustained activation of the UPR due to hypoxia, nutrient deprivation, and increased demand for protein synthesis, alters the UPR program such that additional perturbation of ER homeostasis activates a pro-apoptotic program. Since ubiquitination followed by proteasomal degradation of misfolded proteins within the ER is a central mechanism for restoration of ER homeostasis, inhibitors of this pathway have proven to be valuable anti-cancer therapeutics. Ubiquitin activating enzyme 1(UAE1), activates ubiquitin for transfer to target proteins for proteasomal degradation in conjunction with E2 and E3 enzymes. Inhibition of UAE1 activity in response to TAK-243, leads to an accumulation of misfolded proteins within the ER, thereby aggravating ER stress, leading to DNA damage and arrest of cells in the G2/M phase of the cell cycle. Persistent drug treatment mediates a robust induction of apoptosis following a transient cell cycle arrest. These biological effects of TAK-243 were recapitulated in mouse models of PDAC demonstrating antitumor activity at a dose and schedule that did not exhibit obvious normal tissue toxicity. In vitro as well as studies in mouse models failed to show enhanced efficacy when TAK-243 was combined with ionizing radiation or gemcitabine, providing an impetus for future studies to identify agents that synergize with this class of agents for improved tumor control in PDAC. SIGNIFICANCE: The UAE1 inhibitor TAK-243, mediates activation of the unfolded protein response, accumulation of DNA breaks and apoptosis, providing a rationale for the use as a safe and efficacious anti-cancer therapeutic for PDAC.
    Keywords:  ER stress; Pancreatic cancer; UAE1 Inhibitor
    DOI:  https://doi.org/10.1016/j.tranon.2020.100834