bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒08‒30
ten papers selected by
Susan Logue
University of Manitoba


  1. Front Oncol. 2020 ;10 1100
    Xu L, Zhang W, Zhang XH, Chen X.
      Metastases-the spreading of cancer cells from primary tumors to distant organs, including bone-is often incurable and is the major cause of morbidity in cancer patients. Understanding how cancer cells acquire the ability to colonize to bone and become overt metastases is critical to identify new therapeutic targets and develop new therapies against bone metastases. Recent reports indicate that the endoplasmic reticulum (ER) stress and, as its consequence, the unfolded protein response (UPR) is activated during metastatic dissemination. However, their roles in this process remain largely unknown. In this review, we discuss the recent progress on evaluating the tumorigenic, immunoregulatory and metastatic effects of ER stress and the UPR on bone metastases. We explore new opportunities to translate this knowledge into potential therapeutic strategies for patients with bone metastases.
    Keywords:  ER stress; bone metastases; immunotherapy; metastatic niche; seed and soil; unfolded protein response
    DOI:  https://doi.org/10.3389/fonc.2020.01100
  2. Int J Mol Sci. 2020 Aug 25. pii: E6127. [Epub ahead of print]21(17):
    Ghemrawi R, Khair M.
      The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.
    Keywords:  ER stress; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms21176127
  3. Front Med (Lausanne). 2020 ;7 344
    Barabutis N.
      The unfolded protein response (UPR) is a complex element, destined to protect the cells against a diverse variety of extracellular and intracellular challenges. UPR activation devises highly efficient responses to counteract cellular threats. If those activities fail, it will dictate cellular execution. The current work focuses on the role of UPR in pulmonary function, by immersing into the highly interrelated network that operates toward the endothelial barrier function. A highly sophisticated UPR manipulation shall reveal new therapeutic possibilities against inflammatory lung disease, such as acute lung injury and acute respiratory distress syndrome.
    Keywords:  ER stress; P53; endothelial dysfunction; inflammation; vasculature
    DOI:  https://doi.org/10.3389/fmed.2020.00344
  4. Elife. 2020 Aug 27. pii: e58396. [Epub ahead of print]9
    Stephani M, Picchianti L, Gajic A, Beveridge R, Skarwan E, Sanchez de Medina Hernandez V, Mohseni A, Clavel M, Zeng Y, Naumann C, Matuszkiewicz M, Turco E, Loefke C, Li B, Dürnberger G, Schutzbier M, Chen HT, Abdrakhmanov A, Savova A, Chia KS, Djamei A, Schaffner I, Abel S, Jiang L, Mechtler K, Ikeda F, Martens S, Clausen T, Dagdas Y.
      Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the ER. Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control in the ER.
    Keywords:  A. thaliana; cell biology; human; plant biology; viruses
    DOI:  https://doi.org/10.7554/eLife.58396
  5. BMC Genomics. 2020 Aug 26. 21(1): 590
    Lytrivi M, Ghaddar K, Lopes M, Rosengren V, Piron A, Yi X, Johansson H, Lehtiö J, Igoillo-Esteve M, Cunha DA, Marselli L, Marchetti P, Ortsäter H, Eizirik DL, Cnop M.
      BACKGROUND: Prolonged exposure to elevated free fatty acids induces β-cell failure (lipotoxicity) and contributes to the pathogenesis of type 2 diabetes. In vitro exposure of β-cells to the saturated free fatty acid palmitate is a valuable model of lipotoxicity, reproducing features of β-cell failure observed in type 2 diabetes. In order to map the β-cell response to lipotoxicity, we combined RNA-sequencing of palmitate-treated human islets with iTRAQ proteomics of insulin-secreting INS-1E cells following a time course exposure to palmitate.RESULTS: Crossing transcriptome and proteome of palmitate-treated β-cells revealed 85 upregulated and 122 downregulated genes at both transcript and protein level. Pathway analysis identified lipid metabolism, oxidative stress, amino-acid metabolism and cell cycle pathways among the most enriched palmitate-modified pathways. Palmitate induced gene expression changes compatible with increased free fatty acid mitochondrial import and β-oxidation, decreased lipogenesis and modified cholesterol transport. Palmitate modified genes regulating endoplasmic reticulum (ER) function, ER-to-Golgi transport and ER stress pathways. Furthermore, palmitate modulated cAMP/protein kinase A (PKA) signaling, inhibiting expression of PKA anchoring proteins and downregulating the GLP-1 receptor. SLC7 family amino-acid transporters were upregulated in response to palmitate but this induction did not contribute to β-cell demise. To unravel critical mediators of lipotoxicity upstream of the palmitate-modified genes, we identified overrepresented transcription factor binding sites and performed network inference analysis. These identified LXR, PPARα, FOXO1 and BACH1 as key transcription factors orchestrating the metabolic and oxidative stress responses to palmitate.
    CONCLUSIONS: This is the first study to combine transcriptomic and sensitive time course proteomic profiling of palmitate-exposed β-cells. Our results provide comprehensive insight into gene and protein expression changes, corroborating and expanding beyond previous findings. The identification of critical drivers and pathways of the β-cell lipotoxic response points to novel therapeutic targets for type 2 diabetes.
    Keywords:  Beta-cells; Endoplasmic reticulum stress; Free fatty acids; Lipid metabolism; Pancreatic islets; Proteome; RNA-sequencing; Type 2 diabetes
    DOI:  https://doi.org/10.1186/s12864-020-07003-0
  6. Front Cell Dev Biol. 2020 ;8 756
    Reinhard J, Mattes C, Väth K, Radanović T, Surma MA, Klose C, Ernst R.
      The unfolded protein response (UPR) is central to endoplasmic reticulum (ER) homeostasis by controlling its size and protein folding capacity. When activated by unfolded proteins in the ER-lumen or aberrant lipid compositions, the UPR adjusts the expression of hundreds of target genes to counteract ER stress. The proteotoxic drugs dithiothreitol (DTT) and tunicamycin (TM) are commonly used to induce misfolding of proteins in the ER and to study the UPR. However, their potential impact on the cellular lipid composition has never been systematically addressed. Here, we report the quantitative, cellular lipid composition of Saccharomyces cerevisiae during acute, proteotoxic stress in both rich and synthetic media. We show that DTT causes rapid remodeling of the lipidome when used in rich medium at growth-inhibitory concentrations, while TM has only a marginal impact on the lipidome under our conditions of cultivation. We formulate recommendations on how to study UPR activation by proteotoxic stress without interferences from a perturbed lipid metabolism. Furthermore, our data suggest an intricate connection between the cellular growth rate, the abundance of the ER, and the metabolism of fatty acids. We show that Saccharomyces cerevisiae can produce asymmetric lipids with two saturated fatty acyl chains differing substantially in length. These observations indicate that the pairing of saturated fatty acyl chains is tightly controlled and suggest an evolutionary conservation of asymmetric lipids and their biosynthetic machineries.
    Keywords:  DTT; Ire1; UPR; asymmetric lipids; lipid bilayer stress; lipidomics; proteotoxic stress; tunicamycin
    DOI:  https://doi.org/10.3389/fcell.2020.00756
  7. Int J Mol Sci. 2020 Aug 26. pii: E6146. [Epub ahead of print]21(17):
    Eura Y, Miyata T, Kokame K.
      Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a quality control system that induces the degradation of ER terminally misfolded proteins. The ERAD system consists of complexes of multiple ER membrane-associated and luminal proteins that function cooperatively. We aimed to reveal the role of Derlin-3 in the ERAD system using the liver, pancreas, and kidney obtained from different mouse genotypes. We performed coimmunoprecipitation and sucrose density gradient centrifugation to unravel the dynamic nature of ERAD complexes. We observed that Derlin-3 is exclusively expressed in the pancreas, and its deficiency leads to the destabilization of Herp and accumulation of ERAD substrates. Under normal conditions, Complex-1a predominantly contains Herp, Derlin-2, HRD1, and SEL1L, and under ER stress, Complex-1b contains Herp, Derlin-3 (instead of Derlin-2), HRD1, and SEL1L. Complex-2 is upregulated under ER stress and contains Derlin-1, Derlin-2, p97, and VIMP. Derlin-3 deficiency suppresses the transition of Derlin-2 from Complex-1a to Complex-2 under ER stress. In the pancreas, Derlin-3 deficiency blocks Derlin-2 transition. In conclusion, the composition of ERAD complexes is tissue-specific and changes in response to ER stress in a Derlin-3-dependent manner. Derlin-3 may play a key role in changing ERAD complex compositions to overcome ER stress.
    Keywords:  Derlin-1; Derlin-2; Derlin-3; ER stress; ERAD; ERAD complex; HRD1; Herp
    DOI:  https://doi.org/10.3390/ijms21176146
  8. Nat Commun. 2020 Aug 27. 11(1): 4286
    Sudhakar JN, Lu HH, Chiang HY, Suen CS, Hwang MJ, Wu SY, Shen CN, Chang YM, Li FA, Liu FT, Shui JW.
      Intracellular galectins are carbohydrate-binding proteins capable of sensing and repairing damaged lysosomes. As in the physiological conditions glycosylated moieties are mostly in the lysosomal lumen but not cytosol, it is unclear whether galectins reside in lysosomes, bind to glycosylated proteins, and regulate lysosome functions. Here, we show in gut epithelial cells, galectin-9 is enriched in lysosomes and predominantly binds to lysosome-associated membrane protein 2 (Lamp2) in a Asn(N)-glycan dependent manner. At the steady state, galectin-9 binding to glycosylated Asn175 of Lamp2 is essential for functionality of lysosomes and autophagy. Loss of N-glycan-binding capability of galectin-9 causes its complete depletion from lysosomes and defective autophagy, leading to increased endoplasmic reticulum (ER) stress preferentially in autophagy-active Paneth cells and acinar cells. Unresolved ER stress consequently causes cell degeneration or apoptosis that associates with colitis and pancreatic disorders in mice. Therefore, lysosomal galectins maintain homeostatic function of lysosomes to prevent organ pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-020-18102-7
  9. Int J Mol Sci. 2020 Aug 24. pii: E6088. [Epub ahead of print]21(17):
    Ruiz A, Zuazo J, Ortiz-Sanz C, Luchena C, Matute C, Alberdi E.
      Sephin1 is a derivative of guanabenz that inhibits the dephosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α) and therefore may enhance the integrated stress response (ISR), an adaptive mechanism against different cellular stresses, such as accumulation of misfolded proteins. Unlike guanabenz, Sephin1 provides neuroprotection without adverse effects on the α2-adrenergic system and therefore it is considered a promising pharmacological therapeutic tool. Here, we have studied the effects of Sephin1 on N-methyl-D-aspartic acid (NMDA) receptor signaling which may modulate the ISR and contribute to excitotoxic neuronal loss in several neurodegenerative conditions. Time-course analysis of peIF2α levels after NMDA receptor overactivation showed a delayed dephosphorylation that occurred in the absence of activating transcription factor 4 (ATF4) and therefore independently of the ISR, in contrast to that observed during endoplasmic reticulum (ER) stress induced by tunicamycin and thapsigargin. Similar to guanabenz, Sephin1 completely blocked NMDA-induced neuronal death and was ineffective against AMPA-induced excitotoxicity, whereas it did not protect from experimental ER stress. Interestingly, both guanabenz and Sephin1 partially but significantly reduced NMDA-induced cytosolic Ca2+ increase, leading to a complete inhibition of subsequent calpain activation. We conclude that Sephin1 and guanabenz share common strong anti-excitotoxic properties with therapeutic potential unrelated to the ISR.
    Keywords:  NMDA; Sephin1; calcium; calpain; excitotoxicity; guanabenz; integrated stress response
    DOI:  https://doi.org/10.3390/ijms21176088
  10. Nat Commun. 2020 Aug 26. 11(1): 4254
    Lee TH, Yeh CF, Lee YT, Shih YC, Chen YT, Hung CT, You MY, Wu PC, Shentu TP, Huang RT, Lin YS, Wu YF, Lin SJ, Lu FL, Tsao PN, Lin TH, Lo SC, Tseng YS, Wu WL, Chen CN, Wu CC, Lin SL, Sperling AI, Guzy RD, Fang Y, Yang KC.
      Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.
    DOI:  https://doi.org/10.1038/s41467-020-18047-x