bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒12‒22
seven papers selected by
Susan Logue
University of Manitoba

  1. Cell J. 2020 Oct;22(3): 394-400
    Wang X, Han Y, Hu G, Guo J, Chen H.
      Objective: Endoplasmic reticulum (ER) stress causes an adaptive response initiated by protein kinase RNA-like ER kinase (PERK), Ire1 and ATF6. It has been reported that these upstream regulators induce microRNAs. The current study was designed to find a novel microRNA that mediates ER stress components and finally contributes to cell fate decision.Materials and Methods: In this experimental study, miR-706 levels were checked under different conditions of ER stress induced by Thapsigargin, Tunicamycin or low glucose media. PERK and ATF4 were knocked-down by administration of lentivirus-mediated short hairpin RNA to explore the effect of ER stress related proteins on miR-706 expression. The effect of miR-706 on caspase activity and apoptosis inhibitor 1 (CAAP1) levels were examined by using mimic-miR-706. The role of CAAP1 in inhibiting cell death (measured by Annexin V staining) and contributing to patient overall survival (measured by Kaplan-Meier estimate) were further confirmed by antimiR- 706 and CAAP1 knock-down.
    Results: We showed that Thapsigargin or Tunicamycin triggered ER stress leading to the induction of miR-706. miR-706 induction is dependent on PERK and its downstream regulator ATF4, as knocking-down of PERK and ATF4 suppressed miR-706 induction in response to ER stress. Knocking-down of miR-706 reduces cell death triggered by ER stress, indicating that miR-706 is pro-cell death microRNA. We further identified CAAP1 as a miR-706 target in regulating ER stress initiated cell death.
    Conclusion: Collectively, our results pointed to an ER signaling network consisting of proteins, microRNA and novel target.
    Keywords:  Activating Transcription Factor 4; Caspase Activity and Apoptosis Inhibitor 1; Endoplasmic Reticulum Stress; Protein Kinase RNA-Like ER Kinase; miR-706
  2. Semin Cancer Biol. 2019 Dec 12. pii: S1044-579X(19)30394-3. [Epub ahead of print]
    Bhardwaj M, Leli NM, Koumenis C, Amaravadi RK.
      Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic reticulum (ER) stress, which can be counterbalanced by triggering the unfolded protein response (UPR) which is considered the canonical ER stress response. The UPR is characterized by three major proteins that lead to specific changes in transcriptional and translational programs in stressed cells. Activation of the UPR can induce apoptosis, but also can induce cytoprotective programs such as autophagy. There is increasing appreciation for the role that UPR-induced autophagy plays in supporting tumorigenesis and cancer therapy resistance. More recently several new pathways that connect cell stresses, components of the UPR and autophagy have been reported, which together can be viewed as non-canonical ER stress responses. Here we review recent findings on the molecular mechanisms by which canonical and non-canonical ER stress responses can activate cytoprotective autophagy and contribute to tumor growth and therapy resistance. Autophagy has been identified as a druggable pathway, however the components of autophagy (ATG genes) have proven difficult to drug. It may be the case that targeting the UPR or non-canonical ER stress programs can more effectively block cytoprotective autophagy to enhance cancer therapy. A deeper understanding of these pathways could provide new therapeutic targets in cancer.
    Keywords:  Canonical endoplasmic reticulum stress; autophagy; cancer; non-canonical endoplasmic reticulum stress; unfolded protein response
  3. FEBS J. 2019 Dec 17.
    Sahu RK, Saha N, Das L, Sahu PK, Sariki SK, Tomar RS.
      Chromatin remodeling complexes are multi-subunit assemblies, each containing a catalytic ATPase-translocase that is capable of mobilizing nucleosomes to alter the chromatin structure. SWI/SNF remodeling complexes with higher DNA translocation efficiency evict histones or slide the nucleosomes away from each other making DNA accessible for transcription and repair machinery. Chromatin remodeling at the promoter of stress-responsive genes by SWI/SNF becomes necessary during the heat and proteotoxic stress. While the involvement of SWI/SNF in transcription of stress-responsive genes has been studied extensively, the regulation of proteostasis by SWI/SNF is not well understood. This study demonstrates critical functions of SWI/SNF in response to cadmium-induced proteotoxic stress. Deletion of either ATPase-translocase subunit of SWI/SNF complex (Swi2/Snf2) or a regulatory subunit Swi3 abrogates the clearance of cadmium-induced protein aggregates. Our results suggest that Snf2 and Swi3 regulate the protein folding in endoplasmic reticulum (ER) that reduces the chances of forming unfolded protein aggregates under the proteotoxic stress of cadmium. The Ire1 mediated unfolded protein response (UPR) maintains ER homeostasis by upregulating the expression of chaperones and ER-associated degradation (ERAD) components. We found that Snf2 maintains normal oxidative environment essential for Ire1 activity. Deletion of SNF2 reduced the Ire1 activity and UPR, indicating involvement of Snf2 in Ire1 mediated ER proteostasis. Together, these findings suggest that SWI/SNF complex regulates ER homeostasis and protein folding crucial for tolerating proteotoxic stress.
    Keywords:  Cadmium; Ire1; Oxidative stress; SWI/SNF; unfolded protein response
  4. Dis Model Mech. 2019 Dec 18. pii: dmm.041426. [Epub ahead of print]
    Clark EM, Nonarath HJT, Bostrom JR, Link BA.
      Induction of endoplasmic reticulum (ER) stress is associated with diverse developmental and degenerative diseases. Modified ER homeostasis causes activation of conserved stress pathways at the ER called the unfolded protein response (UPR). ATF6 is a transcription factor activated during ER stress as part of a coordinated UPR. ATF6 resides at the ER, and upon activation is transported to the Golgi apparatus where it is cleaved by proteases to create an amino-terminal cytoplasmic fragment (ATF6f). ATF6f translocates to the nucleus to activate transcriptional targets. Here, we describe establishment and validation of zebrafish reporter lines for ATF6 activity. These transgenic lines are based on a defined and multimerized ATF6 consensus site which drives either eGFP or destabilized eGFP (d2GFP), enabling dynamic study of ATF6 activity during development and disease. The results show that the reporter is specific for the ATF6 pathway, active during development, and induced in disease models known to engage UPR. Specifically, during development, ATF6 activity is highest in the lens, skeletal muscle, fins, and gills. The reporter is also activated by common chemical inducers of ER stress including tunicamycin, thapsigargin, and brefeldin A, as well as by heat shock. In both an ALS and a cone dystrophy model, ATF6 reporter expression is induced in spinal cord interneurons or photoreceptors, respectively, suggesting a role for ATF6 response in multiple neurodegenerative diseases. Collectively our results show these ATF6 reporters can be used to monitor ATF6 activity changes throughout development and in zebrafish models of disease.
    Keywords:  ATF6; Endoplasmic reticulum stress; Neurodegeneration; Unfolded protein response; Zebrafish
  5. Cell Death Dis. 2019 Dec 20. 10(12): 959
    Jeon SJ, Ahn JH, Halder D, Cho HS, Lim JH, Jun SY, Lee JJ, Yoon JY, Choi MH, Jung CR, Kim JM, Kim NS.
      Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.
  6. J Biol Chem. 2019 Dec 17. pii: jbc.RA119.010378. [Epub ahead of print]
    Witham CM, Dassanayake HG, Paxman AL, Stevens KLP, Baklous L, White PF, Black AL, Steuart RFL, Stirling CJ, Schulz BL, Mousley CJ.
      The endoplasmic reticulum (ER) is the entry point to the secretory pathway and major site of protein biogenesis. Translocation of secretory and integral membrane proteins across or into the ER membrane occurs via the evolutionarily conserved Sec61 complex, a heterotrimeric channel that comprises the Sec61p/Sec61α, Sss1p/Sec61γ and Sbh1p/Sec61β subunits. In addition to forming a protein conducting channel, the Sec61 complex also functions to maintain the ER permeability barrier, preventing the mass free flow of essential ER enriched molecules and ions. Loss in Sec61 integrity is detrimental and implicated in the progression of disease. The Sss1p/Sec61γ C-terminus is juxtaposed to the key gating module of Sec61p/Sec61α and we hypothesise it is important for gating the ER translocon. The ER stress response was found to be constitutively induced in two temperature sensitive sss1 mutants (sss1ts ) that are still proficient to conduct ER translocation. A screen to identify intergenic mutations that allow for sss1ts cells to grow at 37oC suggests the ER permeability barrier to be compromised in these mutants.  We propose the extreme C-terminus of Sss1p/Sec61γ is an essential component of the gating module of the ER translocase and is required to maintain the ER permeability barrier.
    Keywords:  Sec61complex; Sss1p/Sec61 γ; Translocon gating; endoplasmic reticulum (ER); endoplasmic reticulum stress (ER stress); endoplasmic-reticulum-associated protein degradation (ERAD); gating; translocation
  7. Elife. 2019 Dec 17. pii: e43302. [Epub ahead of print]8
    Kitakaze K, Taniuchi S, Kawano E, Hamada Y, Miyake M, Oyadomari M, Kojima H, Kosako H, Kuribara T, Yoshida S, Hosoya T, Oyadomari S.
      The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. Finally, IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, our data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.
    Keywords:  ER stress; biochemistry; cell biology; chemical biology; chemical chaperone; human; proteotoxicity