bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021–05–23
sixteen papers selected by
Susan Logue, University of Manitoba
  1. An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation.
  2. Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.
  3. Yeast FIT2 homolog is necessary to maintain cellular proteostasis and membrane lipid homeostasis.
  4. USP22 promotes HER2-driven mammary carcinoma aggressiveness by suppressing the unfolded protein response.
  5. IL-26 mediates epidermal growth factor receptor-tyrosine kinase inhibitor resistance through endoplasmic reticulum stress signaling pathway in triple-negative breast cancer cells.
  6. Foot-and-mouth disease virus induces PERK mediated autophagy to suppress antiviral interferon response.
  7. Stbd1 promotes glycogen clustering during endoplasmic reticulum stress and supports survival of mouse myoblasts.
  8. Calcium as a reliable marker for the quantitative assessment of endoplasmic reticulum stress in live cells.
  9. Retrograde signaling mediates an adaptive survival response to endoplasmic reticulum stress.
  10. Redox and Inflammatory Signaling, the Unfolded Protein Response, and the Pathogenesis of Pulmonary Hypertension.
  11. Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy.
  12. Modulating the ER stress response attenuates neurodegeneration in a C. elegans model of spinal muscular atrophy.
  13. PKD2 deficiency suppresses amino acid biosynthesis in ADPKD by impairing the PERK-TBL2-eIF2ɑ-ATF4 pathway.
  14. Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression.
  15. The Unfolded Protein Response and Autophagy on the Crossroads of Coronaviruses Infections.
  16. LncRNAs induce oxidative stress and spermatogenesis by regulating endoplasmic reticulum genes and pathways.
  1. J Biol Chem. 2021 May 14. pii: S0021-9258(21)00574-3. [Epub ahead of print] 100781
    An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation.
    Daniela Ricci, Stephen Tutton, Ilaria Marrocco, Mingjie Ying, Daniel Blumenthal, Daniela Eletto, Jade Vargas, Sarah Boyle, Hossein Fazelinia, Lei Qian, Krishna Suresh, Deanne Taylor, James C Paton, Adrienne W Paton, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Ravi Radhakrishnan, Tali Gidalevitz, Yair Argon.
      The unfolded protein response (UPR) plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1α is a major transducer that conveys endoplasmic reticulum (ER) stress via biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that, upon sensing unfolded proteins via its ER luminal domain, IRE1α dimerizes and then oligomerizes (often visualized as clustering). Once assembled, the kinase domain trans-autophosphorylates a neighboring IRE1α, inducing a conformational change that activates the RNase effector domain. However, the full details of how the signal is transmitted are not known. Here, we describe a previously unrecognized role for helix αK, located between the kinase and RNase domains of IRE1α, in conveying this critical conformational change. Using constructs containing mutations within this inter-domain helix, we show that distinct substitutions affect oligomerization, kinase activity and the RNase activity of IRE1α differentially. Furthermore, using both biochemical and computational methods, we found that different residues at position 827 specify distinct conformations at distal sites of the protein, such as in the RNase domain. Importantly, an RNase-inactive mutant, L827P, can still dimerize with wild type monomers, but this mutation inactivates the wild type molecule and renders leukemic cells more susceptible to stress. We surmise that helix αK is a conduit for the activation of IRE1α in response to stress.
    Keywords:  IRE1 oligomerization; Kinase RNase interdomain helix; RNase activity; conformational change; differential autophosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2021.100781
  2. Biochem Soc Trans. 2021 May 18. pii: BST20200861. [Epub ahead of print]
    Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.
    Hannah Bolland, Tiffany S Ma, Syafiq Ramlee, Kristijan Ramadan, Ester M Hammond.
      Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant to radiation. The biological response to radiobiological hypoxia is one of few physiologically relevant stresses that activates both the unfolded protein and DNA damage responses (UPR and DDR). Links between these pathways have been identified in studies carried out in normoxia. Based in part on these previous studies and recent work from our laboratory, we hypothesised that the biological response to hypoxia likely includes overlap between the DDR and UPR. While inhibition of the DDR is a recognised strategy for improving radiation response, the possibility of achieving this through targeting the UPR has not been realised. We carried out a systematic review to identify links between the DDR and UPR, in human cell lines exposed to <2% O2. Following PRISMA guidance, literature from January 2010 to October 2020 were retrieved via Ovid MEDLINE and evaluated. A total of 202 studies were included. LAMP3, ULK1, TRIB3, CHOP, NOXA, NORAD, SIAH1/2, DYRK2, HIPK2, CREB, NUPR1, JMJD2B, NRF2, GSK-3B, GADD45a, GADD45b, STAU1, C-SRC, HK2, CAV1, CypB, CLU, IGFBP-3 and SP1 were highlighted as potential links between the hypoxic DDR and UPR. Overall, we identified very few studies which demonstrate a molecular link between the DDR and UPR in hypoxia, however, it is clear that many of the molecules highlighted warrant further investigation under radiobiological hypoxia as these may include novel therapeutic targets to improve radiotherapy response.
    Keywords:  DDR; ER stress; UPR; hypoxia; radiation; replication stress
    DOI:  https://doi.org/10.1042/BST20200861
  3. J Cell Sci. 2020 Jan 01. pii: jcs.248526. [Epub ahead of print]
    Yeast FIT2 homolog is necessary to maintain cellular proteostasis and membrane lipid homeostasis.
    Wei Sheng Yap, Peter Shyu, Maria Laura Gaspar, Stephen A Jesch, Charlie Marvalim, William A Prinz, Susan A Henry, Guillaume Thibault.
      Lipid droplets (LDs) are implicated in conditions of lipid and protein dysregulation. The fat storage inducing transmembrane (FIT) family induces LD formation. Here, we establish a model system to study the role of S. cerevisiae FIT homologues (ScFIT), SCS3 and YFT2, in proteostasis and stress response pathways. While LD biogenesis and basal endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) remain unaltered in ScFIT mutants, SCS3 was found essential for proper stress-induced UPR activation and for viability in the absence of the sole yeast UPR transducer IRE1. Devoid of a functional UPR, muted SCS3 exhibited accumulation of triacylglycerol within the ER along with aberrant LD morphology, suggesting a UPR-dependent compensatory mechanism. Additionally, SCS3 was necessary to maintain phospholipid homeostasis. Strikingly, global protein ubiquitination and the turnover of both ER and cytoplasmic misfolded proteins is impaired in ScFITΔ cells, while a screen for interacting partners of Scs3 identifies components of the proteostatic machinery as putative targets. Together, our data support a model where ScFITs play an important role in lipid metabolism and proteostasis beyond their defined roles in LD biogenesis.
    Keywords:  Endoplasmic reticulum-associated degradation (ERAD); Lipid droplet; Phospholipid metabolism; Proteostasis; Scs3; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1242/jcs.248526
  4. Oncogene. 2021 May 18.
    USP22 promotes HER2-driven mammary carcinoma aggressiveness by suppressing the unfolded protein response.
    Evangelos Prokakis, Anna Dyas, Regina Grün, Sonja Fritzsche, Upasana Bedi, Zahra B Kazerouni, Robyn L Kosinsky, Steven A Johnsen, Florian Wegwitz.
      The Ubiquitin-Specific Protease 22 (USP22) is a deubiquitinating subunit of the mammalian SAGA transcriptional co-activating complex. USP22 was identified as a member of the so-called "death-from-cancer" signature predicting therapy failure in cancer patients. However, the importance and functional role of USP22 in different types and subtypes of cancer remain largely unknown. In the present study, we leveraged human cell lines and genetic mouse models to investigate the role of USP22 in HER2-driven breast cancer (HER2+-BC) and demonstrate for the first time that USP22 is required for the tumorigenic properties in murine and human HER2+-BC models. To get insight into the underlying mechanisms, we performed transcriptome-wide gene expression analyses and identified the Unfolded Protein Response (UPR) as a pathway deregulated upon USP22 loss. The UPR is normally induced upon extrinsic or intrinsic stresses that can promote cell survival and recovery if shortly activated or programmed cell death if activated for an extended period. Strikingly, we found that USP22 actively suppresses UPR induction in HER2+-BC cells by stabilizing the major endoplasmic reticulum (ER) chaperone HSPA5. Consistently, loss of USP22 renders tumor cells more sensitive to apoptosis and significantly increases the efficiency of therapies targeting the ER folding capacity. Together, our data suggest that therapeutic strategies targeting USP22 activity may sensitize tumor cells to UPR induction and could provide a novel, effective approach to treat HER2+-BC.
    DOI:  https://doi.org/10.1038/s41388-021-01814-5
  5. Cell Death Dis. 2021 May 21. 12(6): 520
    IL-26 mediates epidermal growth factor receptor-tyrosine kinase inhibitor resistance through endoplasmic reticulum stress signaling pathway in triple-negative breast cancer cells.
    Takumi Itoh, Ryo Hatano, Yoshiya Horimoto, Taketo Yamada, Dan Song, Haruna Otsuka, Yuki Shirakawa, Shuji Mastuoka, Noriaki Iwao, Thomas M Aune, Nam H Dang, Yutaro Kaneko, Ko Okumura, Chikao Morimoto, Kei Ohnuma.
      Triple-negative breast cancer (TNBC) has a poor prognosis compared to other breast cancer subtypes. Although epidermal growth factor receptor (EGFR) is overexpressed in TNBC, clinical trials with EGFR inhibitors including tyrosine kinase inhibitors (EGFR-TKI) in TNBC have heretofore been unsuccessful. To develop effective EGFR-targeted therapy for TNBC, the precise mechanisms of EGFR-TKI resistance in TNBC need to be elucidated. In this study, to understand the molecular mechanisms involved in the differences in EGFR-TKI efficacy on TNBC between human and mouse, we focused on the effect of IL-26, which is absent in mice. In vitro analysis showed that IL-26 activated AKT and JNK signaling of bypass pathway of EGFR-TKI in both murine and human TNBC cells. We next investigated the mechanisms involved in IL-26-mediated EGFR-TKI resistance in TNBC. We identified EphA3 as a novel functional receptor for IL-26 in TNBC. IL-26 induced dephosphorylation and downmodulation of EphA3 in TNBC, which resulted in increased phosphorylation of AKT and JNK against EGFR-TKI-induced endoplasmic reticulum (ER) stress, leading to tumor growth. Meanwhile, the blockade of IL-26 overcame EGFR-TKI resistance in TNBC. Since the gene encoding IL-26 is absent in mice, we utilized human IL-26 transgenic (hIL-26Tg) mice as a tumor-bearing murine model to characterize the role of IL-26 in the differential effect of EGFR-TKI in human and mice and to confirm our in vitro findings. Our findings indicate that IL-26 activates the bypass pathway of EGFR-TKI, while blockade of IL-26 overcomes EGFR-TKI resistance in TNBC via enhancement of ER stress signaling. Our work provides novel insights into the mechanisms of EGFR-TKI resistance in TNBC via interaction of IL-26 with its newly identified receptor EphA3, while also suggesting IL-26 as a possible therapeutic target in TNBC.
    DOI:  https://doi.org/10.1038/s41419-021-03787-5
  6. J Cell Sci. 2020 Jan 01. pii: jcs.240622. [Epub ahead of print]
    Foot-and-mouth disease virus induces PERK mediated autophagy to suppress antiviral interferon response.
    H B Ranjitha, Veena Ammanathan, Neha Guleria, Madhusudan Hosamani, B P Sreenivasa, V V Dhanesh, Rashmi Santhoshkumar, B K Chandrasekhar Sagar, B P Mishra, R K Singh, Aniket Sanyal, Ravi Manjithaya, Suresh H Basagoudanavar.
      Foot-and-mouth disease virus (FMDV) is a picornavirus that causes contagious acute infection in cloven-hoofed animals. FMDV replication associated viral protein expression induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR), in turn inducing autophagy to restore cellular homeostasis. We observed that inhibition of BiP, a master regulator of ER stress and UPR, decreased FMDV infection confirming their involvement. Further, we show that the FMDV infection induces UPR mainly through PKR-like ER kinase (PERK)-mediated pathway. Knockdown of PERK and chemical inhibition of PERK activation resulted in decreased expression of FMDV proteins along with the reduction of autophagy marker protein LC3B-II. There are conflicting reports on the role of autophagy in FMDV multiplication. Our study systematically demonstrates that during FMDV infection, PERK mediated UPR stimulated an increased level of endogenous LC3B-II and turnover of SQSTM1, thus confirming the activation of functional autophagy. Modulation of UPR and autophagy by pharmacological and genetic approaches resulted in reduced viral progeny, by enhancing antiviral interferon response. Taken together, this study underscores the prospect of exploring the PERK mediated autophagy as an antiviral target.
    Keywords:  Autophagy; Foot-and-mouth disease virus; Interferon; LC3; P-eIF2α; PERK; Unfolded protein response
    DOI:  https://doi.org/10.1242/jcs.240622
  7. J Cell Sci. 2020 Jan 01. pii: jcs.244855. [Epub ahead of print]
    Stbd1 promotes glycogen clustering during endoplasmic reticulum stress and supports survival of mouse myoblasts.
    Andria A Lytridou, Anthi Demetriadou, Melina Christou, Louiza Potamiti, Nikolas P Mastroyiannopoulos, Kyriacos Kyriacou, Leonidas A Phylactou, Anthi Drousiotou, Petros P Petrou.
      Imbalances in endoplasmic reticulum (ER) homeostasis provoke a condition known as ER stress and activate the unfolded protein response (UPR) pathway, an evolutionary conserved cell survival mechanism. Here, we show that mouse myoblasts respond to UPR activation by stimulating glycogenesis and the formation of α-amylase-degradable, glycogen-containing, ER structures. We demonstrate that, the glycogen-binding protein Stbd1 is markedly upregulated through the PERK signalling branch of the UPR pathway and is required for the build-up of glycogen structures in response to ER stress activation. In the absence of ER stress, Stbd1 overexpression is sufficient to induce glycogen clustering but does not stimulate glycogenesis. Glycogen structures induced by ER stress are degraded under conditions of glucose restriction through a process which does not depend on autophagosome-lysosome fusion. Furthermore, we provide evidence that failure to induce glycogen clustering during ER stress is associated with enhanced activation of the apoptotic pathway. Our results reveal a so far unknown response of mouse myoblasts to ER stress and uncover a novel specific function of Stbd1 in this process, which may have physiological implications during myogenic differentiation.
    Keywords:  Apoptosis; ER stress; Glycogen; Glycogen synthase; Glycogenin; UPR
    DOI:  https://doi.org/10.1242/jcs.244855
  8. J Biol Chem. 2021 May 14. pii: S0021-9258(21)00572-X. [Epub ahead of print] 100779
    Calcium as a reliable marker for the quantitative assessment of endoplasmic reticulum stress in live cells.
    Paul F Lebeau, Khrystyna Platko, Jae Hyun Byun, Richard C Austin.
      Calcium (Ca2+) is an essential mineral of endoplasmic reticulum (ER) luminal biochemistry due to the Ca2+-dependence of ER-resident chaperones charged with folding de novo proteins that transit this cellular compartment. ER Ca2+ depletion reduces the ability of chaperones to properly fold the proteins entering the ER, thus leading to an accumulation of misfolded proteins and the onset of a state known as ER stress. However, not all conditions that cause ER stress do so in a manner dependent on ER Ca2+ depletion. Agents like tunicamycin (TM) inhibit the glycosylation of de novo polypeptides, a key step in the maturation process of newly synthesized proteins. Despite this established effect of TM, our understanding of how such conditions modulate ER Ca2+ levels is still limited. In the present study, we report that a variety of ER stress-inducing agents that have not been known to directly alter ER Ca2+ homeostasis can also cause a marked reduction in ER Ca2+ levels. Consistent with these observations, protecting against ER stress using small chemical chaperones, such as 4PBA and TUDCA, also attenuated ER Ca2+ depletion caused by these agents. We also describe a novel high-throughput and low-cost assay for the rapid quantification of ER stress using ER Ca2+ levels as a surrogate marker. This report builds on our understanding of ER Ca2+ levels in the context of ER stress, and also provides the scientific community with a new, reliable tool to study this important cellular process in vitro.
    Keywords:  Calcium; Mag-Fluo-4; endoplasmic reticulum stress (ER stress); unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.jbc.2021.100779
  9. J Cell Sci. 2020 Jan 01. pii: jcs.241539. [Epub ahead of print]
    Retrograde signaling mediates an adaptive survival response to endoplasmic reticulum stress.
    Imadeddin Hijazi, Jeffrey Knupp, Amy Chang.
      One major cause of endoplasmic reticulum (ER) stress is homeostatic imbalance between biosynthetic protein folding and protein folding capacity. Cells utilize mechanisms such as the unfolded protein response (UPR) to cope with ER stress. Nevertheless, when ER stress is prolonged or severe, cell death may occur, accompanied by production of mitochondrial reactive oxygen species (ROS). Using a yeast model, we describe an innate, adaptive response to ER stress to increase select mitochondrial proteins, O2 consumption, and cell survival. The mitochondrial response allows cells to resist additional ER stress. ER stress-induced mitochondrial response is mediated by activation of retrograde (RTG) signaling to enhance anapleurotic reactions of the TCA cycle. Mitochondrial response to ER stress is accompanied by inactivation of the conserved TORC1 pathway, and activation of Snf1/AMPK, the conserved energy sensor and regulator of metabolism. Our results provide new insight into the role of respiration in cell survival in the face of ER stress, and should help in developing therapeutic strategies to limit cell death in disorders linked to ER stress.
    Keywords:  ER stress; Endoplasmic reticulum; Mitochondria; Yeast
    DOI:  https://doi.org/10.1242/jcs.241539
  10. Adv Exp Med Biol. 2021 ;1304 333-373
    Redox and Inflammatory Signaling, the Unfolded Protein Response, and the Pathogenesis of Pulmonary Hypertension.
    Adiya Katseff, Raed Alhawaj, Michael S Wolin.
      Protein folding overload and oxidative stress disrupt endoplasmic reticulum (ER) homeostasis, generating reactive oxygen species (ROS) and activating the unfolded protein response (UPR). The altered ER redox state induces further ROS production through UPR signaling that balances the cell fates of survival and apoptosis, contributing to pulmonary microvascular inflammation and dysfunction and driving the development of pulmonary hypertension (PH). UPR-induced ROS production through ER calcium release along with NADPH oxidase activity results in endothelial injury and smooth muscle cell (SMC) proliferation. ROS and calcium signaling also promote endothelial nitric oxide (NO) synthase (eNOS) uncoupling, decreasing NO production and increasing vascular resistance through persistent vasoconstriction and SMC proliferation. C/EBP-homologous protein further inhibits eNOS, interfering with endothelial function. UPR-induced NF-κB activity regulates inflammatory processes in lung tissue and contributes to pulmonary vascular remodeling. Conversely, UPR-activated nuclear factor erythroid 2-related factor 2-mediated antioxidant signaling through heme oxygenase 1 attenuates inflammatory cytokine levels and protects against vascular SMC proliferation. A mutation in the bone morphogenic protein type 2 receptor (BMPR2) gene causes misfolded BMPR2 protein accumulation in the ER, implicating the UPR in familial pulmonary arterial hypertension pathogenesis. Altogether, there is substantial evidence that redox and inflammatory signaling associated with UPR activation is critical in PH pathogenesis.
    Keywords:  Antioxidant signaling; Cytokines; Endothelial dysfunction; Endothelial injury; NADPH oxidase; Oxidative stress; Protein folding; Pulmonary vascular remodeling; Vasoconstriction
    DOI:  https://doi.org/10.1007/978-3-030-68748-9_17
  11. Front Immunol. 2021 ;12 671998
    Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy.
    Maud Lemarié, Fabrice Chatonnet, Gersende Caron, Thierry Fest.
      Antibody therapy, where artificially-produced immunoglobulins (Ig) are used to treat pathological conditions such as auto-immune diseases and cancers, is a very innovative and competitive field. Although substantial efforts have been made in recent years to obtain specific and efficient antibodies, there is still room for improvement especially when considering a precise tissular targeting or increasing antigen affinity. A better understanding of the cellular and molecular steps of terminal B cell differentiation, in which an antigen-activated B cell becomes an antibody secreting cell, may improve antibody therapy. In this review, we use our recently published data about human B cell differentiation, to show that the mechanisms necessary to adapt a metamorphosing B cell to its new secretory function appear quite early in the differentiation process i.e., at the pre-plasmablast stage. After characterizing the molecular pathways appearing at this stage, we will focus on recent findings about two main processes involved in antibody production: unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. We'll show that many genes coding for factors involved in UPR and ER stress are induced at the pre-plasmablast stage, sustaining our hypothesis. Finally, we propose to use this recently acquired knowledge to improve productivity of industrialized therapeutic antibodies.
    Keywords:  B cell differentiation; ER stress; RNA-seq; UPR; mAbs
    DOI:  https://doi.org/10.3389/fimmu.2021.671998
  12. Dis Model Mech. 2020 Jan 01. pii: dmm.041350. [Epub ahead of print]
    Modulating the ER stress response attenuates neurodegeneration in a C. elegans model of spinal muscular atrophy.
    James J Doyle, Celine Vrancx, Claudia Maios, Audrey Labarre, Shunmoogum A Patten, J Alex Parker.
      Spinal muscular atrophy is (SMA) is a devastating, autosomal recessive neuromuscular disease resulting in muscle atrophy, neurodegeneration, and is the leading genetic cause of infant death. SMA arises when there are homozygous deletion mutations in the human SMN1 gene, leading to a decrease in corresponding SMN1 protein. Although SMN1 is expressed across multiple tissue types, much of the previous research into SMA focused on the neuronal aspect of the disease, overlooking many of the potential non-neuronal aspects of the disease. Therefore, we sought to address this gap in knowledge by modeling SMA in the nematode Caenorhabditis elegans. We used a previously uncharacterized allele which resulted in the onset of mild SMA-like phenotypes allowing us to monitor the onset of phenotypes at different stages. We observed that these mutant animals recapitulated many key features of the human disease, and most importantly, we observed that muscle dysfunction precedes neurodegeneration. Furthermore, we tested the therapeutic efficacy of targeting endoplasmic reticulum (ER) stress in non-neuronal cells and found it to be more effective than targeting ER stress in neuronal cells. We also found that the most potent therapeutic potential came from a combination of ER- and neuromuscular junction (NMJ)-targeting drugs. Together, our results suggest an important non-neuronal component of SMA pathology and highlight new considerations for therapeutic intervention.
    Keywords:  C. elegans; ER stress; Genetics; Muscle pathology; Spinal muscular atrophy
    DOI:  https://doi.org/10.1242/dmm.041350
  13. Biochem Biophys Res Commun. 2021 May 17. pii: S0006-291X(21)00782-8. [Epub ahead of print]561 73-79
    PKD2 deficiency suppresses amino acid biosynthesis in ADPKD by impairing the PERK-TBL2-eIF2ɑ-ATF4 pathway.
    Xingquan Zhou, Hui Xiong, Yi Lu, Meijuan Geng, Yumei Lu, Lirong Zhang, Xu Zhu.
      Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism remain elusive. Here we report that amino acid biosynthesis is reprogrammed in Pkd2-knockout mouse kidneys via a defective PERK-eIF2ɑ-ATF4 pathway. Transcriptomic analysis revealed that the amino acid biosynthesis pathways such as serine, arginine and cysteine were impaired, and associated critical enzymes were downregulated in Pkd2-knockout mouse kidneys. ATF4 and CHOP, transcription factors downstream of the endoplasmic reticulum (ER) stress sensor PERK, were identified as master regulators of these enzymes' expression. PKD2 deficiency impaired the expression of ATF4 and amino acid synthesis enzymes in RCTEC cells under ER stress. Mechanistically, as an ER-resident protein, PKD2 interacts with TBL2, which functions as an adaptor bridging eIF2ɑ to PERK. PKD2 depletion impaired the recruitment of eIF2ɑ to TBL2, thus impeding activation of the PERK-eIF2ɑ-ATF4 pathway and downstream amino acid biosynthesis. These findings illuminate a molecular mechanism linking the PKD2-mediated PERK-eIF2ɑ-ATF4 pathway and amino acid metabolic reprogramming in ADPKD.
    Keywords:  ADPKD; ATF4; Amino acid biosynthesis; PKD2; TBL2
    DOI:  https://doi.org/10.1016/j.bbrc.2021.05.012
  14. Sci Rep. 2021 May 17. 11(1): 10435
    Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression.
    Dávid Pethő, Zoltán Hendrik, Annamária Nagy, Lívia Beke, Andreas Patsalos, László Nagy, Szilárd Póliska, Gábor Méhes, Csaba Tóth, László Potor, John W Eaton, Harry S Jacob, György Balla, József Balla, Tamás Gáll.
      Hemorrhage and hemolysis with subsequent heme release are implicated in many pathologies. Endothelial cells (ECs) encounter large amount of free heme after hemolysis and are at risk of damage from exogenous heme. Here we show that hemorrhage aggravates endoplasmic reticulum (ER) stress in human carotid artery plaques compared to healthy controls or atheromas without hemorrhage as demonstrated by RNA sequencing and immunohistochemistry. In EC cultures, heme also induces ER stress. In contrast, if cultured ECs are pulsed with heme arginate, cells become resistant to heme-induced ER (HIER) stress that is associated with heme oxygenase-1 (HO-1) and ferritin induction. Knocking down HO-1, HO-2, biliverdin reductase, and ferritin show that HO-1 is the ultimate cytoprotectant in acute HIER stress. Carbon monoxide-releasing molecules (CORMs) but not bilirubin protects cultured ECs from HIER stress via HO-1 induction, at least in part. Knocking down HO-1 aggravates heme-induced cell death that cannot be counterbalanced with any known cell death inhibitors. We conclude that endothelium and perhaps other cell types can be protected from HIER stress by induction of HO-1, and heme-induced cell death occurs via HIER stress that is potentially involved in the pathogenesis of diverse pathologies with hemolysis and hemorrhage including atherosclerosis.
    DOI:  https://doi.org/10.1038/s41598-021-89713-3
  15. Front Cell Infect Microbiol. 2021 ;11 668034
    The Unfolded Protein Response and Autophagy on the Crossroads of Coronaviruses Infections.
    Elisa B Prestes, Julia C P Bruno, Leonardo H Travassos, Leticia A M Carneiro.
      The ability to sense and adequately respond to variable environmental conditions is central for cellular and organismal homeostasis. Eukaryotic cells are equipped with highly conserved stress-response mechanisms that support cellular function when homeostasis is compromised, promoting survival. Two such mechanisms - the unfolded protein response (UPR) and autophagy - are involved in the cellular response to perturbations in the endoplasmic reticulum, in calcium homeostasis, in cellular energy or redox status. Each of them operates through conserved signaling pathways to promote cellular adaptations that include re-programming transcription of genes and translation of new proteins and degradation of cellular components. In addition to their specific functions, it is becoming increasingly clear that these pathways intersect in many ways in different contexts of cellular stress. Viral infections are a major cause of cellular stress as many cellular functions are coopted to support viral replication. Both UPR and autophagy are induced upon infection with many different viruses with varying outcomes - in some instances controlling infection while in others supporting viral replication and infection. The role of UPR and autophagy in response to coronavirus infection has been a matter of debate in the last decade. It has been suggested that CoV exploit components of autophagy machinery and UPR to generate double-membrane vesicles where it establishes its replicative niche and to control the balance between cell death and survival during infection. Even though the molecular mechanisms are not fully elucidated, it is clear that UPR and autophagy are intimately associated during CoV infections. The current SARS-CoV-2 pandemic has brought renewed interest to this topic as several drugs known to modulate autophagy - including chloroquine, niclosamide, valinomycin, and spermine - were proposed as therapeutic options. Their efficacy is still debatable, highlighting the need to better understand the molecular interactions between CoV, UPR and autophagy.
    Keywords:  autophagy; coronavirus; host-pathogen interaction; integrated stress response; unfolded protein response
    DOI:  https://doi.org/10.3389/fcimb.2021.668034
  16. Aging (Albany NY). 2021 May 06. 13
    LncRNAs induce oxidative stress and spermatogenesis by regulating endoplasmic reticulum genes and pathways.
    Tie-Cheng Sun, Yi Zhang, Kun Yu, Yao Li, Hong Yu, Shan-Jie Zhou, Ya-Peng Wang, Shou-Long Deng, Li Tian.
      Oligozoospermia or low sperm count is a leading cause of male infertility worldwide. Despite decades of work on non-coding RNAs (ncRNAs) as regulators of spermatogenesis, fertilization, and male fertility, the literature on the function of long non-coding RNAs (lncRNAs) in human oligozoospermia is scarce. We integrated lncRNA and mRNA sequencing data from 12 human normozoospermic and oligozoospermic samples and comprehensively analyzed the function of differentially expressed lncRNAs (DE lncRNAs) and mRNAs (DE mRNAs) in male infertility. The target genes of DE lncRNAs were identified using a Gaussian graphical model. Gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were primarily enriched in protein transport and localization to the endoplasmic reticulum (ER). The lncRNA-mRNA co-expression network revealed cis- and trans-regulated target genes of lncRNAs. The transcriptome data implicated DE lncRNAs and DE mRNAs and their target genes in the accumulation of unfolded proteins in sperm ER, PERK-EIF2 pathway-induced ER stress, oxidative stress, and sperm cell apoptosis in individuals with oligozoospermia. These findings suggest that the identified lncRNAs and pathways could serve as effective therapeutic targets for male infertility.
    Keywords:  apoptosis; long noncoding RNAs; oligozoospermia; oxidative stress; spermatogenesis
    DOI:  https://doi.org/10.18632/aging.202971
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:30.