bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021–08–15
ten papers selected by
Matías Eduardo González Quiroz, Worker’s Hospital
  1. Structural and molecular bases to IRE1 activity modulation.
  2. ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model.
  3. The special unfolded protein response in plasma cells.
  4. Fat body Ire1 regulates lipid homeostasis through the Xbp1s-FoxO axis in Drosophila.
  5. IGF-1 induces IRE1-XBP1-dependent endoplasmic reticulum biogenesis in bovine mammary epithelial cells.
  6. Cas9 Expression Causes p53 Pathway Activation and TP53 Mutations.
  7. Natural compounds modulate the autophagy with potential implication of stroke.
  8. The Deubiquitinase USP22 Modulates Regulatory T-cell Function.
  9. p62-containing, proteolytically active nuclear condensates, increase the efficiency of the ubiquitin-proteasome system.
  10. Importance of Community-Level Interventions During the COVID-19 Pandemic: Lessons from Sub-Saharan Africa.
  1. Biochem J. 2021 Aug 13. 478(15): 2953-2975
    Structural and molecular bases to IRE1 activity modulation.
    Timothy Langlais, Diana Pelizzari-Raymundo, Sayyed Jalil Mahdizadeh, Nicolas Gouault, Francois Carreaux, Eric Chevet, Leif A Eriksson, Xavier Guillory.
      The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.
    Keywords:  ER stress; IRE1; structure activity relationship (SAR); structure-based drug design (SBDD); unfolded protein response
    DOI:  https://doi.org/10.1042/BCJ20200919
  2. Sci Rep. 2021 Aug 11. 11(1): 16356
    ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model.
    Eun-Jin Lee, Priscilla Chan, Leon Chea, Kyle Kim, Randal J Kaufman, Jonathan H Lin.
      Retinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 (Atf6), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin (Rho+/P23H) mice. Significantly increased rhodopsin protein levels were found in Atf6-/-Rho+/P23H retinas compared to Atf6+/-Rho+/P23H retinas at early ages (~ P12), while rhodopsin mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young Atf6-/-Rho+/P23H retinas, and photoreceptor layer thickness was unchanged at this early age in Rho+/P23H mice lacking Atf6. By contrast, older Atf6-/-Rho+/P23H mice developed significantly increased retinal degeneration in comparison to Atf6+/-Rho+/P23H mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that Atf6 is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of Atf6 ultimately accelerates retinal degeneration in P23H-KI mice.
    DOI:  https://doi.org/10.1038/s41598-021-95895-7
  3. Immunol Rev. 2021 Aug 08.
    The special unfolded protein response in plasma cells.
    Daniela Ricci, Tali Gidalevitz, Yair Argon.
      The high rate of antibody production places considerable metabolic and folding stress on plasma cells (PC). Not surprisingly, they rely on the unfolded protein response (UPR), a universal signaling, and transcriptional network that monitors the health of the secretory pathway and mounts cellular responses to stress. Typically, the UPR utilizes three distinct stress sensors in the ER membrane, each regulating a subset of targets to re-establish homeostasis. PC use a specialized UPR scheme-they preemptively trigger the UPR via developmental signals and suppress two of the sensors, PERK and ATF6, relying on IRE1 alone. The specialized PC UPR program is tuned to the specific needs at every stage of development-from early biogenesis of secretory apparatus, to massive immunoglobulin expression later. Furthermore, the UPR in PC integrates with other pathways essential in a highly secretory cell-mTOR pathway that ensures efficient synthesis, autophagosomes that recycle components of the synthetic machinery, and apoptotic signaling that controls cell fate in the face of excessive folding stress. This specialized PC program is not shared with other secretory cells, for reasons yet to be defined. In this review, we give a perspective into how and why PC need such a unique UPR program.
    Keywords:  anticipatory unfolded protein response; autophagy; expansion of secretory apparatus; inactivation of sensors
    DOI:  https://doi.org/10.1111/imr.13012
  4. iScience. 2021 Aug 20. 24(8): 102819
    Fat body Ire1 regulates lipid homeostasis through the Xbp1s-FoxO axis in Drosophila.
    Peng Zhao, Ping Huang, Tongfu Xu, Xiaoxiang Xiang, Ying Sun, Jingqi Liu, Cheng Yan, Lei Wang, Jiamei Gao, Shang Cui, Xiangdong Wang, Lixing Zhan, Haiyun Song, Jingnan Liu, Wei Song, Yong Liu.
      The endoplasmic reticulum (ER)-resident transmembrane protein kinase/RNase Ire1 is a conserved sensor of the cellular unfolded protein response and has been implicated in lipid homeostasis, including lipid synthesis and transport, across species. Here we report a novel catabolic role of Ire1 in regulating lipid mobilization in Drosophila. We found that Ire1 is activated by nutrient deprivation, and, importantly, fat body-specific Ire1 deficiency leads to increased lipid mobilization and sensitizes flies to starvation, whereas fat body Ire1 overexpression results in the opposite phenotypes. Genetic interaction and biochemical analyses revealed that Ire1 regulates lipid mobilization by promoting Xbp1s-associated FoxO degradation and suppressing FoxO-dependent lipolytic programs. Our results demonstrate that Ire1 is a catabolic sensor and acts through the Xbp1s-FoxO axis to hamper the lipolytic response during chronic food deprivation. These findings offer new insights into the conserved Ire1 regulation of lipid homeostasis.
    Keywords:  Cell biology; Lipid; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2021.102819
  5. J Dairy Sci. 2021 Aug 04. pii: S0022-0302(21)00783-9. [Epub ahead of print]
    IGF-1 induces IRE1-XBP1-dependent endoplasmic reticulum biogenesis in bovine mammary epithelial cells.
    Mst Mamuna Sharmin, Satoko Hayashi, Makoto Miyaji, Hiroshi Ishizaki, Hiroki Matsuyama, Satoshi Haga, Shinichi Yonekura.
      Insulin-like growth factor-1 (IGF-1) plays a key role in proliferation and galactopoiesis in mammary epithelial cells (MEC), but its definitive functions on endoplasmic reticulum (ER) during protein synthesis remain unknown. The present study aimed to elucidate the effects of IGF-1 on ER biogenesis in MEC in vitro and examined the expression of ER biogenesis-associated genes in the mammary gland during early lactation. We treated mammary alveolar cells-large T antigen cells (immortalized bovine MEC line established via stable transfection with simian virus-40 large T-antigen) with IGF-1 and examined ER biogenesis using the fluorescence intensity of an ER tracker and quantitative real-time PCR. We found IGF-1 significantly increased ER tracker staining and upregulated mRNA levels of ER biogenesis-related genes, such as CHKA (choline kinase α), PCYT1A (choline-phosphate cytidylyltransferase A), and SURF4 (surfeit locus protein 4). We focused on unfolded protein response to explore molecular mechanisms by which IGF-1 induces ER biogenesis. We found IGF-1 significantly increased mRNA levels of the XBP1 splicing form (XBP1s). Based on western blot analysis, IGF-1 induced the expression of (inositol-requiring kinase 1 α) protein, upstream of XBP1s, and phosphorylated-IRE1α. The inhibition of IRE1 endoribonuclease activity with 4-methylumbelliferone 8-carbaldehyde (4μ8C) significantly suppressed the increase in ER tracker fluorescence and ER biogenesis-related gene expression induced by IGF-1. Also, IGF-1-induced XBP1s and ER biogenesis-associated gene expression was inhibited by rapamycin, an inhibitor of mTORC1 (mammalian target of rapamycin complex 1), indicating that IRE1-XBP1 activation by IGF-1 is mediated by mTORC1. Moreover, to clarify the expression of XBP1s and ER biogenesis-associated genes expression under normal physiological conditions, mammary gland tissue from biopsies of dairy cows during late gestation and lactation were analyzed. In vivo data highlighted the significant increases in the mRNA levels of XBP1s and ER biogenesis-related genes in mammary gland tissue immediately after calving through 6 wk of lactation. The mRNA levels of IGF1R (IGF-1 receptor) in mammary glands increased during 6 wk of lactation. Therefore, the present study indicated for the first time that IGF-1 induces ER biogenesis by activating the IRE1-XBP1 axis under the regulation of mTORC1 in bovine MEC line.
    Keywords:  IGF-1; endoplasmic reticulum biogenesis; mammary epithelial cell; unfolded protein response
    DOI:  https://doi.org/10.3168/jds.2021-20268
  6. Cancer Discov. 2020 Jul;10(7): 903
    Cas9 Expression Causes p53 Pathway Activation and TP53 Mutations.
      p53-pathway activation, inactivating TP53 mutations, and DNA damage were common with Cas9 expression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-081
  7. Acta Pharm Sin B. 2021 Jul;11(7): 1708-1720
    Natural compounds modulate the autophagy with potential implication of stroke.
    Anil Ahsan, Mengru Liu, Yanrong Zheng, Wenping Yan, Lin Pan, Yue Li, Shijia Ma, Xingxian Zhang, Ming Cao, Zhanxun Wu, Weiwei Hu, Zhong Chen, Xiangnan Zhang.
      Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.
    Keywords:  AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; AMPK, 5′-adenosine monophosphate-activated protein kinase; ATF6, activating transcription factor 6; ATG, autophagy related genes; Autophagy; BCL-2, B-cell lymphoma 2; BNIP3L, BCL2/adenovirus; COPII, coat protein complex II; Cerebral ischemia; ER, endoplasmic reticulum; FOXO, forkhead box O; FUNDC1, FUN14 domain containing 1; GPCR, G-protein coupled receptor; HD, Huntington's disease; IPC, ischemic preconditioning; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; LAMP, lysosomal-associated membrane protein; LC3, light chain 3; LKB1, liver kinase B1; Lysosomal activation; Mitochondria; Mitophagy; Natural compounds; Neurological disorders; Neuroprotection; OGD/R, oxygen and glucose deprivation-reperfusion; PD, Parkinson's disease; PERK, protein kinase R (PKR)-like endoplasmic reticulum kinase; PI3K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; SQSTM1, sequestosome 1; TFEB, transcription factor EB; TIGAR, TP53-induced glycolysis and apoptosis regulator; ULK, Unc-51- like kinase; Uro-A, urolithin A; eIF2a, eukaryotic translation-initiation factor 2; mTOR, mechanistic target of rapamycin; ΔΨm, mitochondrial membrane potential
    DOI:  https://doi.org/10.1016/j.apsb.2020.10.018
  8. Cancer Discov. 2020 Jul;10(7): OF11
    The Deubiquitinase USP22 Modulates Regulatory T-cell Function.
      USP22 positively regulated transcription factor FOXP3 activity in mouse regulatory T (Treg) cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-070
  9. Proc Natl Acad Sci U S A. 2021 Aug 17. pii: e2107321118. [Epub ahead of print]118(33):
    p62-containing, proteolytically active nuclear condensates, increase the efficiency of the ubiquitin-proteasome system.
    Afu Fu, Victoria Cohen-Kaplan, Noa Avni, Ido Livneh, Aaron Ciechanover.
      Degradation of a protein by the ubiquitin-proteasome system (UPS) is a multistep process catalyzed by sequential reactions. Initially, ubiquitin is conjugated to the substrate in a process mediated by concerted activity of three enzymes; the last of them-a ubiquitin ligase (E3)-belongs to a family of several hundred members, each recognizing a few specific substrates. This is followed by repeated addition of ubiquitin moieties to the previously conjugated one to generate a ubiquitin chain that serves as a recognition element for the proteasome, which then degrades the substrate. Ubiquitin is recycled via the activity of deubiquitinating enzymes (DUBs). It stands to reason that efficiency of such a complex process would depend on colocalization of the different components in an assembly that allows the reactions to be carried out sequentially and processively. Here we describe nuclear condensates that are dynamic in their composition. They contain p62 as an essential component. These assemblies are generated by liquid-liquid phase separation (LLPS) and also contain ubiquitinated targets, 26S proteasome, the three conjugating enzymes, and DUBs. Under basal conditions, they serve as efficient centers for proteolysis of nuclear proteins (e.g., c-Myc) and unassembled subunits of the proteasome, suggesting they are involved in cellular protein quality control. Supporting this notion is the finding that such foci are also involved in degradation of misfolded proteins induced by heat and oxidative stresses, following recruitment of heat shock proteins and their associated ubiquitin ligase CHIP.
    Keywords:  LLPS condensates; p62; proteasome; protein degradation; ubiquitin
    DOI:  https://doi.org/10.1073/pnas.2107321118
  10. Am J Trop Med Hyg. 2021 Aug 09. pii: tpmd201533. [Epub ahead of print]
    Importance of Community-Level Interventions During the COVID-19 Pandemic: Lessons from Sub-Saharan Africa.
    Ayomide Owoyemi, Elvis Anyaehiechukwu Okolie, Kasarachi Omitiran, Uchenna Anderson Amaechi, Babasola Olufemi Sodipo, Olufemi Ajumobi, Chukwudi Ernest Nnaji, Ijeoma Nkem Okedo-Alex.
      Community-level strategies are important in ensuring adequate control of disease outbreaks especially in sub-Saharan African countries. Learning from public health responses to previous infectious disease outbreaks is important in shaping these responses to COVID-19. This study aims to highlight and summarize the evidence from community-level interventions during infectious disease outbreaks in sub-Saharan Africa (SSA). We conducted a scoping review of published literature on community-level interventions and strategies adopted in different infectious disease outbreaks in SSA. To obtain relevant studies, we searched EMBASE, CINAHL, MEDLINE, and Google Scholar in August 2020. Our search was based on the combination of keywords such as coronavirus, flu, Ebola, community, rural, strategies, impact, effectiveness, feasibility, Africa, developing countries, and SSA. Studies that met the inclusion criteria were selected and synthesized under the following distinct themes: health education, sensitization, and communications; surveillance; and service delivery. Our review highlights community-based strategies that have been tried and tested with varying outcomes for different outbreaks in different sub-Saharan African communities, we believe they will inform the selection of strategies to adopt in managing the COVID-19 pandemic at the community level. The important aspects of these strategies were highlighted, requirements for successful implementation and the possible challenges that might be encountered were also discussed. Achieving control of the COVID-19 pandemic in sub-Saharan African communities, will require concerted community-based and community-led strategies, which in turn rely on the availability of necessary socioeconomic resources, and the contextual adaption of these interventions.
    DOI:  https://doi.org/10.4269/ajtmh.20-1533
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