bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒11‒22
nine papers selected by
Susan Logue
University of Manitoba


  1. Nat Rev Cancer. 2020 Nov 19.
    Chen X, Cubillos-Ruiz JR.
      Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.
    DOI:  https://doi.org/10.1038/s41568-020-00312-2
  2. Cell Death Differ. 2020 Nov 20.
    Duwaerts CC, Siao K, Soon RK, Her C, Iwawaki T, Kohno K, Mattis AN, Maher JJ.
      X-box binding protein-1 (XBP1) is a transcription factor that plays a central role in controlling cellular responses to endoplasmic reticulum (ER) stress. Under stress conditions, the transcriptionally active form of XBP1 is generated via splicing of Xbp1 mRNA by the ER-resident protein inositol-requiring enzyme-1 (IRE1α). Genetic deletion of XBP1 has multiple consequences: some resulting from the loss of the transcription factor per se, and others related to compensatory activation of IRE1α. The objective of the current study was to investigate the effects of XBP1 deletion in adult mouse liver and determine to what extent they are direct or indirect. XBP1 was deleted from hepatocytes in adult Xbp1fl/fl mice using AAV8-Transthyretin-Cre (Xbp1Δhep). Xbp1Δhep mice exhibited no liver disease at baseline, but developed acute biochemical and histologic liver injury in response to a dietary challenge with fructose for 4 weeks. Fructose-mediated liver injury in Xbp1Δhep mice coincided with heightened IRE1α activity, as demonstrated by Xbp1 mRNA splicing, JNK activation, and regulated IRE1α-dependent RNA decay (RIDD). Activation of eIF2α was also evident, with associated up-regulation of the pro-apoptotic molecules CHOP, BIM, and PUMA. To determine whether the adverse consequences of liver-specific XBP1 deletion were due to XBP1 loss or heightened IRE1α activity, we repeated a fructose challenge in mice with liver-specific deletion of both XBP1 and IRE1α (Xbp1Δhep;Ire1aΔhep). Xbp1Δhep;Ire1aΔhep mice were protected from fructose-mediated liver injury and failed to exhibit any of the signs of ER stress seen in mice lacking XBP1 alone. The protective effect of IRE1α deletion persisted even with long-term exposure to fructose. Xbp1Δhep mice developed liver fibrosis at 16 weeks, but Xbp1Δhep;Ire1aΔhep mice did not. Overall, the results indicate that the deleterious effects of hepatocyte-specific XBP1 deletion are due primarily to hyperactivation of IRE1α. They support further exploration of IRE1α as a contributor to acute and chronic liver diseases.
    DOI:  https://doi.org/10.1038/s41418-020-00671-1
  3. Oncogene. 2020 Nov 17.
    Sari IN, Yang YG, Wijaya YT, Jun N, Lee S, Kim KS, Bajaj J, Oehler VG, Kim SH, Choi SY, Park SH, Kim DW, Reya T, Han J, Kwon HY.
      Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.
    DOI:  https://doi.org/10.1038/s41388-020-01547-x
  4. J Biol Chem. 2020 Nov 18. pii: jbc.RA120.016083. [Epub ahead of print]
    Deng J, Bai X, Tang H, Pang S.
      DNA damage triggers the cellular adaptive response to arrest proliferation and repair DNA damage; when damage is too severe to be repaired, apoptosis is initiated to prevent the spread of genomic insults. However, how cells endure DNA damage to maintain cell function remains largely unexplored. By using C. elegans as a model, we report that DNA damage elicits cell maintenance programs including the endoplasmic reticulum (ER) unfolded protein response (UPRER). Mechanistically, sublethal DNA damage unexpectedly suppresses apoptotic genes in C. elegans, which in turn increases the activity of the IRE-1/XBP-1 branch of the UPRER by elevating unsaturated phosphatidylcholine (PC). In addition, UPRER activation requires silencing of the lipid regulator SKN-1. DNA damage suppresses SKN-1 activity to increase unsaturated PC and activate UPRER. These findings reveal the UPRER activation as an organismal adaptive response that is important to maintain cell function during DNA damage.
    Keywords:  Caenorhabditis elegans (C. elegans); DNA damage response; SKN-1; apoptotic genes; endoplasmic reticulum stress (ER stress); fatty acid; phosphatidylcholine
    DOI:  https://doi.org/10.1074/jbc.RA120.016083
  5. FEBS Lett. 2020 Nov 18.
    Liu Y, Tan Z, Yang Y.
      Endoplasmic reticulum (ER) stress is a cell state in which misfolded or unfolded proteins are aberrantly accumulated in the ER. ER stress induces an evolutionarily conserved adaptive response, named ER stress response, that deploys a self-regulated machinery to maintain cellular proteostasis. However, compared to its well-established canonical activation mechanism, the negative feedback mechanisms regulating the ER stress response remain unclear and no accepted methods or markers have been established. Several studies have documented that both endogenous and exogenous insults can induce ER stress in cancer. Based on this evidence, small molecule inhibitors targeting ER stress response have been designed to kill cancer cells, with some of them showing excellent curative effects. Here, we review recent advances in our understanding of negative feedback of ER stress response and compare the markers used to date. We also summarize therapeutic inhibitors targeting ER stress response and highlight the promises and challenges ahead.
    Keywords:  ER stress response; ER-phagy; ERAD; UPR; anti-cancer strategy; feedback regulation
    DOI:  https://doi.org/10.1002/1873-3468.14000
  6. Molecules. 2020 Nov 16. pii: E5336. [Epub ahead of print]25(22):
    Khan AA, Allemailem KS, Almatroudi A, Almatroodi SA, Mahzari A, Alsahli MA, Rahmani AH.
      A proper execution of basic cellular functions requires well-controlled homeostasis including correct protein folding. Endoplasmic reticulum (ER) implements such functions by protein reshaping and post-translational modifications. Different insults imposed on cells could lead to ER stress-mediated signaling pathways, collectively called the unfolded protein response (UPR). ER stress is also closely linked with oxidative stress, which is a common feature of diseases such as stroke, neurodegeneration, inflammation, metabolic diseases, and cancer. The level of ER stress is higher in cancer cells, indicating that such cells are already struggling to survive. Prolonged ER stress in cancer cells is like an Achilles' heel, if aggravated by different agents including nanoparticles (NPs) may be exhausted off the pro-survival features and can be easily subjected to proapoptotic mode. Different types of NPs including silver, gold, silica, graphene, etc. have been used to augment the cytotoxicity by promoting ER stress-mediated cell death. The diverse physico-chemical properties of NPs play a great role in their biomedical applications. Some special NPs have been effectively used to address different types of cancers as these particles can be used as both toxicological or therapeutic agents. Several types of NPs, and anticancer drug nano-formulations have been engineered to target tumor cells to enhance their ER stress to promote their death. Therefore, mitigating ER stress in cancer cells in favor of cell death by ER-specific NPs is extremely important in future therapeutics and understanding the underlying mechanism of how cancer cells can respond to NP induced ER stress is a good choice for the development of novel therapeutics. Thus, in depth focus on NP-mediated ER stress will be helpful to boost up developing novel pro-drug candidates for triggering pro-death pathways in different cancers.
    Keywords:  ER stress mediated diseases; anticancer drugs; drug nanoformulation; endoplasmic reticulum stress; nanoparticles
    DOI:  https://doi.org/10.3390/molecules25225336
  7. Cells. 2020 Nov 17. pii: E2495. [Epub ahead of print]9(11):
    Costa CAD, Manaa WE, Duplan E, Checler F.
      Parkinson's disease (PD) is a multifactorial age-related movement disorder in which defects of both mitochondria and the endoplasmic reticulum (ER) have been reported. The unfolded protein response (UPR) has emerged as a key cellular dysfunction associated with the etiology of the disease. The UPR involves a coordinated response initiated in the endoplasmic reticulum that grants the correct folding of proteins. This review gives insights on the ER and its functioning; the UPR signaling cascades; and the link between ER stress, UPR activation, and physiopathology of PD. Thus, post-mortem studies and data obtained by either in vitro and in vivo pharmacological approaches or by genetic modulation of PD causative genes are described. Further, we discuss the relevance and impact of the UPR to sporadic and genetic PD pathology.
    Keywords:  Parkinson’s disease; genetics; reticulum endoplasmic; unfolded protein response
    DOI:  https://doi.org/10.3390/cells9112495
  8. Life Sci. 2020 Nov 11. pii: S0024-3205(20)31493-4. [Epub ahead of print] 118740
    Bashir S, Banday M, Qadri O, Bashir A, Hilal N, Nida-I-Fatima , Rader S, Fazili KM.
      The endoplasmic reticulum is primarily responsible for protein folding and maturation. However, the organelle is subject to varied stress conditions from time to time, which lead to the activation of a signaling program known as the Unfolded Protein Response (UPR) pathway. This pathway, upon sensing any disturbance in the protein-folding milieu sends signals to the nucleus and cytoplasm in order to restore homeostasis. One of the prime UPR signaling sensors is Inositol-requiring enzyme 1 (IRE1); an ER membrane embedded protein with dual enzyme activities, kinase and endoribonuclease. The ribonuclease activity of IRE1 results in Xbp1 splicing in mammals or Hac1 splicing in yeast. However, IRE1 can switch its substrate specificity to the mRNAs that are co-transnationally transported to the ER, a phenomenon known as Regulated IRE1 Dependent Decay (RIDD). IRE1 is also reported to act as a principal molecule that coordinates with other proteins and signaling pathways, which in turn might be responsible for its regulation. The current review highlights studies on IRE1 explaining the structural features and molecular mechanism behind its ribonuclease outputs. The emphasis is also laid on the molecular effectors, which directly or indirectly interact with IRE1 to either modulate its function or connect it to other pathways. This is important in understanding the functional pleiotropy of IRE1, by which it can switch its activity from pro-survival to pro-apoptotic, thus determining the fate of cells.
    Keywords:  Divergent cell fates; ER-stress; Inositol-requiring enzyme 1(IRE1); Regulated IRE1 Dependent Decay (RIDD); Unfolded Protein Response (UPR); X-box protein 1 (Xbp1)
    DOI:  https://doi.org/10.1016/j.lfs.2020.118740
  9. J Biol Chem. 2020 Nov 19. pii: jbc.RA120.016053. [Epub ahead of print]
    Lee SJ, Wang W, Jin L, Lu X, Gao L, Chen Y, Liu T, Emery D, Vukmanic E, Liu Y, Kaplan HJ, Dean D.
      Chronic ER stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates Retinitis Pigmentosa, characterized initially by diminished nighttime and peripheral vision.  Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high resolution color vision utilized for tasks including reading, driving and facial recognition.  If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit to patients with Retinitis Pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO , we find that induction of a Danger-Associated Molecular Pattern (DAMP) "eat me" signal on the surface of mutant rods is correlated with targeting the live cells for programmed cell removal (PrCR) by retinal myeloid cells.  Glucocorticoid therapy leads to replacement of this DAMP with a "don't eat me" immune checkpoint on the rod surface and inhibition of PrCR.  Surviving rods then continue to promote glucose transport to cones, maintaining their viability.
    Keywords:  photoreceptor; photosynthetic pigment; retina; retinal degeneration; rhodopsin
    DOI:  https://doi.org/10.1074/jbc.RA120.016053