bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒09‒05
seven papers selected by
Susan Logue
University of Manitoba
  1. Neuronal regulated ire-1-dependent mRNA decay controls germline differentiation in Caenorhabditis elegans.
  2. Influenza A viruses balance ER stress with host protein synthesis shutoff.
  3. The role of endoplasmic reticulum stress in astrocytes.
  4. ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury.
  5. CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level.
  6. Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation.
  7. The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging.
  1. Elife. 2021 Sep 03. pii: e65644. [Epub ahead of print]10
    Neuronal regulated ire-1-dependent mRNA decay controls germline differentiation in Caenorhabditis elegans.
    Mor Levi-Ferber, Rewayd Shalash, Adrien Le-Thomas, Yehuda Salzberg, Maor Shurgi, Jennifer Ic Benichou, Avi Ashkenazi, Sivan Henis-Korenblit.
      Understanding the molecular events that regulate cell pluripotency versus acquisition of differentiated somatic cell fate is fundamentally important. Studies in Caenorhabditis elegans demonstrate that knockout of the germline-specific translation repressor gld-1 causes germ cells within tumorous gonads to form germline-derived teratoma. Previously we demonstrated that endoplasmic reticulum (ER) stress enhances this phenotype to suppress germline tumor progression(Levi-Ferber et al., 2015). Here, we identify a neuronal circuit that non-autonomously suppresses germline differentiation and show that it communicates with the gonad via the neurotransmitter serotonin to limit somatic differentiation of the tumorous germline. ER stress controls this circuit through regulated inositol requiring enzyme-1 (IRE-1)-dependent mRNA decay of transcripts encoding the neuropeptide FLP-6. Depletion of FLP-6 disrupts the circuit's integrity and hence its ability to prevent somatic-fate acquisition by germline tumor cells. Our findings reveal mechanistically how ER stress enhances ectopic germline differentiation and demonstrate that regulated Ire1-dependent decay can affect animal physiology by controlling a specific neuronal circuit.
    Keywords:  C. elegans; ER stress; IRE1; RIDD; cell biology; developmental biology; germline; neuronal circuit; pluripotency; teratoma
    DOI:  https://doi.org/10.7554/eLife.65644
  2. Proc Natl Acad Sci U S A. 2021 Sep 07. pii: e2024681118. [Epub ahead of print]118(36):
    Influenza A viruses balance ER stress with host protein synthesis shutoff.
    Beryl Mazel-Sanchez, Justyna Iwaszkiewicz, Joao P P Bonifacio, Filo Silva, Chengyue Niu, Shirin Strohmeier, Davide Eletto, Florian Krammer, Gene Tan, Vincent Zoete, Benjamin G Hale, Mirco Schmolke.
      Excessive production of viral glycoproteins during infections poses a tremendous stress potential on the endoplasmic reticulum (ER) protein folding machinery of the host cell. The host cell balances this by providing more ER resident chaperones and reducing translation. For viruses, this unfolded protein response (UPR) offers the potential to fold more glycoproteins. We postulated that viruses could have developed means to limit the inevitable ER stress to a beneficial level for viral replication. Using a relevant human pathogen, influenza A virus (IAV), we first established the determinant for ER stress and UPR induction during infection. In contrast to a panel of previous reports, we identified neuraminidase to be the determinant for ER stress induction, and not hemagglutinin. IAV relieves ER stress by expression of its nonstructural protein 1 (NS1). NS1 interferes with the host messenger RNA processing factor CPSF30 and suppresses ER stress response factors, such as XBP1. In vivo viral replication is increased when NS1 antagonizes ER stress induction. Our results reveal how IAV optimizes glycoprotein expression by balancing folding capacity.
    Keywords:  CPSF30; ER stress; NS1; influenza virus; neuraminidase
    DOI:  https://doi.org/10.1073/pnas.2024681118
  3. Glia. 2021 Aug 31.
    The role of endoplasmic reticulum stress in astrocytes.
    Savannah G Sims, Rylee N Cisney, Marissa M Lipscomb, Gordon P Meares.
      Astrocytes are glial cells that support neurological function in the central nervous system (CNS), in part, by providing structural support for neuronal synapses and blood vessels, participating in electrical and chemical transmission, and providing trophic support via soluble factors. Dysregulation of astrocyte function contributes to neurological decline in CNS diseases. Neurological diseases are highly heterogeneous but share common features of cellular stress including the accumulation of misfolded proteins. Endoplasmic reticulum (ER) stress has been reported in nearly all neurological and neurodegenerative diseases. ER stress occurs when there is an accumulation of misfolded proteins in the ER lumen and the protein folding demand of the ER is overwhelmed. ER stress initiates the unfolded protein response (UPR) to restore homeostasis by abating protein translation and, if the cell is irreparably damaged, initiating apoptosis. Although protein aggregation and misfolding in neurological disease has been well described, cell-specific contributions of ER stress and the UPR in physiological and disease states are poorly understood. Recent work has revealed a role for active UPR signaling that may drive astrocytes toward a maladaptive phenotype in various model systems. In response to ER stress, astrocytes produce inflammatory mediators, have reduced trophic support, and can transmit ER stress to other cells. This review will discuss the current known contributions and consequences of activated UPR signaling in astrocytes.
    Keywords:  astrocytes; cell signaling; endoplasmic reticulum; glia; protein folding; translation
    DOI:  https://doi.org/10.1002/glia.24082
  4. Cell Death Discov. 2021 Aug 28. 7(1): 223
    ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury.
    Yiming Lei, Sizhe Wan, Huiling Liu, Haoxiong Zhou, Lingjun Chen, Yidong Yang, Bin Wu.
      Acute liver injury (ALI) caused by multiple inflammatory responses is a monocyte-/macrophage-mediated liver injury that is associated with high morbidity and mortality. Liver macrophage activation is a vital event that triggers ALI. However, the mechanism of liver macrophage activation has not been fully elucidated. This study examined the role of β-arrestin1 (ARRB1) in wild-type (WT) and ARRB1-knockout (ARRB1-KO) mouse models of ALI induced by lipopolysaccharide (LPS), and ARRB1-KO mice exhibited more severe inflammatory injury and liver macrophage activation compared to WT mice. We found that LPS treatment reduced the expression level of ARRB1 in Raw264.7 and THP-1 cell lines, and mouse primary hepatic macrophages. Overexpression of ARRB1 in Raw264.7 and THP-1 cell lines significantly attenuated LPS-induced liver macrophage activation, such as transformation in cell morphology and enhanced expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), while downregulation of ARRB1 by small interfering RNA and ARRB1 deficiency in primary hepatic macrophages both aggravated macrophage activation. Moreover, overexpression of ARRB1 suppressed LPS-induced endoplasmic reticulum (ER) stress in liver macrophages, and inhibition of ER stress impeded excessive hepatic macrophage activation induced by downregulation of ARRB1. Our data demonstrate that ARRB1 relieves LPS-induced ALI through the ER stress pathway to regulate hepatic macrophage activation and that ARRB1 may be a potential therapeutic target for ALI.
    DOI:  https://doi.org/10.1038/s41420-021-00615-9
  5. FASEB J. 2021 Oct;35(10): e21908
    CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level.
    Junyang Tan, Yaping Che, Yanyan Liu, Jiaqiao Hu, Wenjun Wang, Liubing Hu, Qinghua Zhou, Hao Wang, Jianshuang Li.
      Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2), a mammalian orthologue of drosophila flamingo, belongs to the cadherin subfamily. CELSR2 mainly function in neural development and cilium polarity. Recent studies showed that the CELSR2 gene is related to many human diseases, including coronary artery disease, idiopathic scoliosis, and cancer. Genome-Wide Association Studies data showed that SNP in the CELSR2-PSRC1-SORT1 gene loci has a strong association with circulating lipid levels and coronary artery disease. However, the function and underlying mechanism of CELSR2 in hepatic lipid metabolism remain unknown. Here, we found that CELSR2 expression is decreased in the liver of NAFLD/NASH patients and db/db mice. Depletion of CELSR2 significantly decreased the lipid accumulation in hepatocytes by suppressing the expression of lipid synthesis enzymes. Moreover, CELSR2 deficiency impaired the physiological unfolded protein response (UPR), which damages the ER homeostasis, and elevates the reactive oxygen species (ROS) level by decreasing the antioxidant expression. Scavenging of ROS by N-acetylcysteine treatment could restore the decreased lipid accumulation of CELSR2 knockdown cells. Furthermore, CELSR2 loss impaired cell survival by suppressing cell proliferation and promoting apoptosis. Our results uncovered a new role of CELSR2 in regulating lipid homeostasis and UPR, suggesting CELSR2 may be a new therapeutic target for non-alcoholic fatty liver disease.
    Keywords:  CELSR2; cell survival; lipid metabolism; unfolded protein response
    DOI:  https://doi.org/10.1096/fj.202100786RR
  6. Nat Commun. 2021 Sep 02. 12(1): 5242
    Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation.
    Shubham Khetan, Susan Kales, Romy Kursawe, Alexandria Jillette, Jacob C Ulirsch, Steven K Reilly, Duygu Ucar, Ryan Tewhey, Michael L Stitzel.
      Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving β cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in β cell transcriptional stress response and T2D genetics.
    DOI:  https://doi.org/10.1038/s41467-021-25514-6
  7. Elife. 2021 09 01. pii: e63453. [Epub ahead of print]10
    The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging.
    Suzanne Angeli, Anna Foulger, Manish Chamoli, Tanuja Harshani Peiris, Akos Gerencser, Azar Asadi Shahmirzadi, Julie Andersen, Gordon Lithgow.
      Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPRmt). Pharmacological or genetic inhibition of the mPTP inhibits the UPRmt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging. Our findings reveal how an mPTP/UPRmt nexus may contribute to aging and age-related diseases and how inhibition of the UPRmt may be protective under certain conditions.
    Keywords:  C. elegans; F-ATP synthase; aging; c-subunit; cell biology; mitochondrial permeability transition pore; mitochondrial unfolded protein response; oscp/atp-3
    DOI:  https://doi.org/10.7554/eLife.63453
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