bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021‒05‒16
nineteen papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital
  1. 3-Acetyldeoxynivalenol induces cell death through endoplasmic reticulum stress in mouse liver.
  2. Hepatocyte steatosis inhibits hepatitis B virus secretion via induction of endoplasmic reticulum stress.
  3. USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites.
  4. Vps34 and TOR Kinases Coordinate HAC1 mRNA Translation in the presence or absence of Ire1-dependent Splicing.
  5. Detecting and Rescuing Stalled Ribosomes.
  6. Unfolded protein response in the activation-induced biological processes of CD8+ T cells.
  7. Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons.
  8. Sex differences and aging: is there a role of brown adipose tissue?
  9. Ubiquitylation in DNA double-strand break repair.
  10. Structures of telomerase at several steps of telomere repeat synthesis.
  11. Zebrafish Cancer Predisposition Models.
  12. Detection of Protein Aggregation using Fluorescence Correlation Spectroscopy.
  13. Endoplasmic reticulum-associated degradation controls virus protein homeostasis that is required for the flavivirus propagation.
  14. Chromosome oscillation promotes Aurora A-dependent Hec1 phosphorylation and mitotic fidelity.
  15. trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway.
  16. Principles of membrane remodeling by dynamic ESCRT-III polymers.
  17. An aged immune system drives senescence and ageing of solid organs.
  18. Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.
  19. Diabetic nephropathy in mice is aggravated by the absence of podocyte IRE1 and is correlated with reduced kidney ADH1 expression.
  1. Environ Pollut. 2021 Apr 27. pii: S0269-7491(21)00820-4. [Epub ahead of print]286 117238
    3-Acetyldeoxynivalenol induces cell death through endoplasmic reticulum stress in mouse liver.
    Hai Jia, Ning Liu, Yunchang Zhang, Chao Wang, Ying Yang, Zhenlong Wu.
      Ingestion of food or cereal products contaminated by deoxynivalenol (DON) and related derivatives poses a threat to the health of humans and animals. However, the toxicity and underlying mechanisms of 3-acetyldeoxynivalenol (3-Ac-DON), an acetylated form of deoxynivalenol, have not been fully elucidated. In the present study, we showed that 3-Ac-DON caused significant oxidative damage, as shown by elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH) in serum, increased lipid peroxidation products, such as hydrogen peroxide (H2O2) and malondialdehyde (MDA), decreased activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). In addition, 3-Ac-DON exposure led to elevated infiltrations of immune cell, increased apoptosis and autophagy in the liver. Interestingly, 3-Ac-DON-resulted apoptosis and liver injury were partially reduced by autophagy inhibitors. Further study showed that 3-Ac-DON-treated mice had altered ultrastructural changes of endoplasmic reticulum (ER), as well as enhanced protein levels of p-IRE1α, p-PERK, and downstream targets, indicating activation of unfolded protein response (UPR) in the liver. Importantly, 3-Ac-DON induced ER stress, oxidative damage, cell death, infiltration of immune cells, and increased mRNA levels of inflammatory cytokines were significantly abolished by 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, indicating a critical role of UPR signaling for the cellular damage of the liver in response to 3-Ac-DON exposure. In conclusion, using mice as an animal model, we showed that 3-Ac-DON exposure impaired the function of liver, as shown by oxidative damage, cell death, and infiltration of immune cell, in which ER stress played an important role. Restoration of the ER function might be a preventive strategy to reduce the deleterious effect of 3-Ac-DON on the liver of animals.
    Keywords:  3-Acetyldeoxynivalenol; 4-Phenylbutyric acid; Apoptosis; Autophagy; ER stress
    DOI:  https://doi.org/10.1016/j.envpol.2021.117238
  2. Mol Cell Biochem. 2021 May 13.
    Hepatocyte steatosis inhibits hepatitis B virus secretion via induction of endoplasmic reticulum stress.
    Qichuang Liu, Maoyuan Mu, Huan Chen, Guoyuan Zhang, Yanqing Yang, Jun Chu, Ying Li, Fangwan Yang, Shide Lin.
      The effects of hepatocyte steatosis on hepatitis B virus (HBV) DNA replication and HBV-related antigen secretion are incompletely understood. The aims of this study are to explore the effects and mechanism of hepatocyte steatosis on HBV replication and secretion. Stearic acid (SA) and oleic acid (OA) were used to induce HepG2.2.15 cell steatosis in this study. The expressions of glucose-regulated protein 78 (GRP78), phosphorylation of protein kinase R-like endoplasmic reticulum (ER) kinase (p-PERK), and eukaryotic translation initiation factor 2α (p-eIF2α) were detected by Western blotting (WB). HBV DNA, HBsAg, and HBeAg in the supernatant were determined by real-time fluorescent polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Intracellular HBV DNA, HBsAg level, and HBV RNA were measured by real-time fluorescent PCR, WB, and real-time quantitative reverse transcriptase-PCR, respectively. The results showed that SA and OA significantly increased intracellular lipid droplets and triglyceride levels. SA and OA significantly induced GRP78, p-PERK, and p-eIF2α expressions from 24 to 72 h. 4-phenylbutyric acid (PBA) alleviated ER stress induced by SA. SA promoted intracellular HBsAg and HBV DNA accumulation; however, it inhibited the transcript of HBV 3.5 kb mRNA and S mRNA. The secretion of HBsAg and HBV DNA inhibited by SA or OA could be partially restored by pretreatment with PBA but not by inhibiting GRP78 expression with siRNA. Hepatocyte steatosis inhibits HBsAg and HBV DNA secretion via induction of ER stress in hepatocytes, but not via induction of GRP78.
    Keywords:  Endoplasmic reticulum stress; HBVDNA; HBsAg; HepG2.2.15 cell; Oleic acid; Stearic acid
    DOI:  https://doi.org/10.1007/s11010-021-04143-z
  3. J Cell Biol. 2021 Jul 05. pii: e202010006. [Epub ahead of print]220(7):
    USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites.
    Peiyuan Chai, Yiru Cheng, Chuyi Hou, Lei Yin, Donghui Zhang, Yingchun Hu, Qingzhou Chen, Pengli Zheng, Junlin Teng, Jianguo Chen.
      The ER tethers tightly to mitochondria and the mitochondrial protein FUNDC1 recruits Drp1 to ER-mitochondria contact sites, subsequently facilitating mitochondrial fission and preventing mitochondria from undergoing hypoxic stress. However, the mechanisms by which the ER modulates hypoxia-induced mitochondrial fission are poorly understood. Here, we show that USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites under hypoxia and promotes hypoxia-induced mitochondrial division. In response to hypoxia, USP19 binds to and deubiquitinates FUNDC1 at ER-mitochondria contact sites, which facilitates Drp1 oligomerization and Drp1 GTP-binding and hydrolysis activities, thereby promoting mitochondrial division. Our findings reveal a unique hypoxia response pathway mediated by an ER protein that regulates mitochondrial dynamics.
    DOI:  https://doi.org/10.1083/jcb.202010006
  4. Mol Cell Biol. 2021 May 10. pii: MCB.00662-20. [Epub ahead of print]
    Vps34 and TOR Kinases Coordinate HAC1 mRNA Translation in the presence or absence of Ire1-dependent Splicing.
    Jagadeesh Kumar Uppala, Sankhajit Bhattacharjee, Madhusudan Dey.
      In the budding yeast Saccharomyces cerevisiae an mRNA, called HAC1, exists in a translationally repressed form in the cytoplasm. Under conditions of cellular stress, such as when unfolded proteins accumulate inside the endoplasmic reticulum (ER), an RNase Ire1 removes an intervening sequence (intron) from the HAC1 mRNA by non-conventional cytosolic splicing. Removal of the intron results in translational de-repression of HAC1 mRNA and production of a transcription factor that activates expressions of many enzymes and chaperones to increase the protein-folding capacity of the cell. Here, we show that Ire1-mediated RNA cleavage requires Watson-Crick base pairs in two RNA hairpins, which are located at the HAC1 mRNA exon-intron junctions. Then, we show that the translational de-repression of HAC1 mRNA can occur independent of cytosolic splicing. These results are obtained from HAC1 variants that translated an active Hac1 protein from the un-spliced mRNA. Additionally, we show that the phosphatidylinositol-3-kinase Vps34 and the nutrient-sensing kinases TOR and GCN2 are key regulators of HAC1 mRNA translation and consequently the ER stress responses. Collectively, our data suggest that the cytosolic splicing and the translational de-repression of HAC1 mRNA are coordinated by unique and parallel networks of signaling pathways.
    DOI:  https://doi.org/10.1128/MCB.00662-20
  5. Trends Biochem Sci. 2021 May 06. pii: S0968-0004(21)00066-9. [Epub ahead of print]
    Detecting and Rescuing Stalled Ribosomes.
    Matthew C J Yip, Sichen Shao.
      Ribosomes that stall inappropriately during protein synthesis harbor proteotoxic components linked to cellular stress and neurodegenerative diseases. Molecular mechanisms that rescue stalled ribosomes must selectively detect rare aberrant translational complexes and process the heterogeneous components. Ribosome-associated quality control pathways eliminate problematic messenger RNAs and nascent proteins on stalled translational complexes. In addition, recent studies have uncovered general principles of stall recognition upstream of quality control pathways and fail-safe mechanisms that ensure nascent proteome integrity. Here, we discuss developments in our mechanistic understanding of the detection and rescue of stalled ribosomal complexes in eukaryotes.
    Keywords:  ribosome collisions; ribosome stalling; ribosome-associated quality control (RQC)
    DOI:  https://doi.org/10.1016/j.tibs.2021.03.008
  6. Pharmacol Res. 2021 May 06. pii: S1043-6618(21)00238-3. [Epub ahead of print]169 105654
    Unfolded protein response in the activation-induced biological processes of CD8+ T cells.
    Yingying Shi, Yichao Lu, Jian You.
      As the central part of cellular immunity, primed CD8+ T cells go through different phases of response including activation, clonal expansion, contraction and steady-state turnover, which is accompanied by a fluctuating level of endoplasmic reticulum stress that leads to the elicitation of unfolded protein response (UPR). In turn, UPR casts profound impacts on the activation-induced biological processes of CD8+ T cells, which may greatly determine the magnitude and quality of T-cell based immunity. However, current understanding of the interconnectivity between UPR and T cell-biology is not comprehensive, with details of manipulation largely unexplored. In this review, the molecular basis of UPR involved in different stages of activated CD8+ T cells and its immunological significance are discussed, with potential strategies of regulation proposed, which may provide instructive guidance for the design and optimization of T cell-based immunotherapy.
    Keywords:  Activation-induced biological processes; CD8(+) T cells; Immunotherapy; Regulation strategy; UPR
    DOI:  https://doi.org/10.1016/j.phrs.2021.105654
  7. J Vis Exp. 2021 Apr 24.
    Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons.
    Carolina Morales, Mariano Bisbal, Mariana Bollo.
      The accumulation of unfolded proteins within the endoplasmic reticulum (ER), caused by any stress condition, triggers the unfolded protein response (UPR) through the activation of specialized sensors. UPR attempts first to restore homeostasis; but if damage persists the signaling induces apoptosis. There is increasing evidence that sustained and unresolved ER stress contributes to many pathological conditions including neurodegenerative diseases. Because the UPR controls cell fate by switching between cytoprotective and apoptotic processes, it is essential to understand the events defining this transition, as well as the elements involved in its modulation. Recently, we demonstrated that abnormal GM2 ganglioside accumulation causes depletion of ER Ca2+ content, which in turn activates PERK (PKR-like-ER kinase), one of the UPR sensors. Furthermore, PERK signaling participates in the neurite atrophy and apoptosis induced by GM2 accumulation. In this respect, we have established an experimental system that allows us to molecularly modulate the expression of downstream PERK components and thus change vulnerability of neurons to undergo neuritic atrophy. We performed knockdown of calcineurin (cytoprotective) and CHOP (pro-apoptotic) expression in rat cortical neuronal cultures. Cells were infected with lentivirus-delivered specific shRNA and then treated with GM2 at different times, fixed and immunostained with anti-MAP2 (microtube-associated protein 2) antibody. Later, cell images were recorded using a fluorescence microscope and total neurite outgrowth was evaluated by using the public domain image processing software ImageJ. The inhibition of expression of those PERK signaling components clearly made it possible to either accelerate or delay the neuritic atrophy induced by ER stress. This approach might be used in cell system models of ER stress to evaluate the vulnerability of neurons to neurite atrophy.
    DOI:  https://doi.org/10.3791/61974
  8. Mol Cell Endocrinol. 2021 May 11. pii: S0303-7207(21)00154-4. [Epub ahead of print] 111310
    Sex differences and aging: is there a role of brown adipose tissue?
    Jessica M Hoffman, Teresa G Valencak.
      In every population across the world, women live significantly longer than men; however, the underlying physiological processes that drive these sex differences in age-specific mortality are largely unknown. Recently, the role of adipose tissue in aging and longevity has been a focus of biomedical research in both humans and rodent models. Specifically, brown adipose tissue, a thermoregulatory tissue originally thought to not exist past infancy in humans, has been shown to potentially play a role in health throughout the lifespan. Females have larger adult brown adipose depots that are not just larger in size but also more efficient in non-shivering thermogenesis. This improved functioning of the brown adipose tissue may potentially lead to improved female health, and we hypothesize that this advantage may be of even bigger significance in the older population. Here, we briefly review what is known about sex differences in aging and how sex differences in brown adipose tissue may be contributing to the female lifespan advantage. These questions have usually been addressed in large experimental studies in rodents as a translational model of human aging. Overall, we propose that a better understanding of the thermogenesis-metabolism nexus is necessary in biomedical research, and sex differences in these factors may contribute to the female longevity bias seen in human populations.
    Keywords:  aging; brown adipose tissue; longevity; sex differences
    DOI:  https://doi.org/10.1016/j.mce.2021.111310
  9. DNA Repair (Amst). 2021 May 07. pii: S1568-7864(21)00085-9. [Epub ahead of print]103 103129
    Ubiquitylation in DNA double-strand break repair.
    Mengfan Tang, Siting Li, Junjie Chen.
      Genome integrity is constantly challenged by various DNA lesions with DNA double-strand breaks (DSBs) as the most cytotoxic lesions. In order to faithfully repair DSBs, DNA damage response (DDR) signaling networks have evolved, which organize many multi-protein complexes to deal with the encountered DNA damage. Spatiotemporal dynamics of these protein complexes at DSBs are mainly modulated by post-translational modifications (PTMs). One of the most well-studied PTMs in DDR is ubiquitylation which can orchestrate cellular responses to DSBs, promote accurate DNA repair, and maintain genome integrity. Here, we summarize the recent advances of ubiquitin-dependent signaling in DDR and discuss how ubiquitylation crosstalks with other PTMs to control fundamental biological processes in DSB repair.
    Keywords:  DNA damage response; Double strand break; homologous recombination (HR); non-homologous end joining (NHEJ); ubiquitylation
    DOI:  https://doi.org/10.1016/j.dnarep.2021.103129
  10. Nature. 2021 May 12.
    Structures of telomerase at several steps of telomere repeat synthesis.
    Yao He, Yaqiang Wang, Baocheng Liu, Christina Helmling, Lukas Sušac, Ryan Cheng, Z Hong Zhou, Juli Feigon.
      Telomerase is unique among the reverse transcriptases in containing a noncoding RNA (known as telomerase RNA (TER)) that includes a short template that is used for the processive synthesis of G-rich telomeric DNA repeats at the 3' ends of most eukaryotic chromosomes1. Telomerase maintains genomic integrity, and its activity or dysregulation are critical determinants of human longevity, stem cell renewal and cancer progression2,3. Previous cryo-electron microscopy structures have established the general architecture, protein components and stoichiometries of Tetrahymena and human telomerase, but our understandings of the details of DNA-protein and RNA-protein interactions and of the mechanisms and recruitment involved remain limited4-6. Here we report cryo-electron microscopy structures of active Tetrahymena telomerase with telomeric DNA at different steps of nucleotide addition. Interactions between telomerase reverse transcriptase (TERT), TER and DNA reveal the structural basis of the determination of the 5' and 3' template boundaries, handling of the template-DNA duplex and separation of the product strand during nucleotide addition. The structure and binding interface between TERT and telomerase protein p50 (a homologue of human TPP17,8) define conserved interactions that are required for telomerase activation and recruitment to telomeres. Telomerase La-related protein p65 remodels several regions of TER, bridging the 5' and 3' ends and the conserved pseudoknot to facilitate assembly of the TERT-TER catalytic core.
    DOI:  https://doi.org/10.1038/s41586-021-03529-9
  11. Front Cell Dev Biol. 2021 ;9 660069
    Zebrafish Cancer Predisposition Models.
    Kim Kobar, Keon Collett, Sergey V Prykhozhij, Jason N Berman.
      Cancer predisposition syndromes are rare, typically monogenic disorders that result from germline mutations that increase the likelihood of developing cancer. Although these disorders are individually rare, resulting cancers collectively represent 5-10% of all malignancies. In addition to a greater incidence of cancer, affected individuals have an earlier tumor onset and are frequently subjected to long-term multi-modal cancer screening protocols for earlier detection and initiation of treatment. In vivo models are needed to better understand tumor-driving mechanisms, tailor patient screening approaches and develop targeted therapies to improve patient care and disease prognosis. The zebrafish (Danio rerio) has emerged as a robust model for cancer research due to its high fecundity, time- and cost-efficient genetic manipulation and real-time high-resolution imaging. Tumors developing in zebrafish cancer models are histologically and molecularly similar to their human counterparts, confirming the validity of these models. The zebrafish platform supports both large-scale random mutagenesis screens to identify potential candidate/modifier genes and recently optimized genome editing strategies. These techniques have greatly increased our ability to investigate the impact of certain mutations and how these lesions impact tumorigenesis and disease phenotype. These unique characteristics position the zebrafish as a powerful in vivo tool to model cancer predisposition syndromes and as such, several have already been created, including those recapitulating Li-Fraumeni syndrome, familial adenomatous polyposis, RASopathies, inherited bone marrow failure syndromes, and several other pathogenic mutations in cancer predisposition genes. In addition, the zebrafish platform supports medium- to high-throughput preclinical drug screening to identify compounds that may represent novel treatment paradigms or even prevent cancer evolution. This review will highlight and synthesize the findings from zebrafish cancer predisposition models created to date. We will discuss emerging trends in how these zebrafish cancer models can improve our understanding of the genetic mechanisms driving cancer predisposition and their potential to discover therapeutic and/or preventative compounds that change the natural history of disease for these vulnerable children, youth and adults.
    Keywords:  cancer; cancer predisposition; genetic models; model organism; p53; zebrafish
    DOI:  https://doi.org/10.3389/fcell.2021.660069
  12. J Vis Exp. 2021 Apr 25.
    Detection of Protein Aggregation using Fluorescence Correlation Spectroscopy.
    Akira Kitamura, Ai Fujimoto, Masataka Kinjo.
      Protein aggregation is a hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and so on. To detect and analyze soluble or diffuse protein oligomers or aggregates, fluorescence correlation spectroscopy (FCS), which can detect the diffusion speed and brightness of a single particle with a single molecule sensitivity, has been used. However, the proper procedure and know-how for protein aggregation detection have not been widely shared. Here, we show a standard procedure of FCS measurement for diffusion properties of aggregation-prone proteins in cell lysate and live cells: ALS-associated 25 kDa carboxyl-terminal fragment of TAR DNA/RNA-binding protein 43 kDa (TDP25) and superoxide dismutase 1 (SOD1). The representative results show that a part of aggregates of green fluorescent protein (GFP)-tagged TDP25 was slightly included in the soluble fraction of murine neuroblastoma Neuro2a cell lysate. Moreover, GFP-tagged SOD1 carrying ALS-associated mutation shows a slower diffusion in live cells. Accordingly, we here introduce the procedure to detect the protein aggregation via its diffusion property using FCS.
    DOI:  https://doi.org/10.3791/62576
  13. J Virol. 2021 May 12. pii: JVI.02234-20. [Epub ahead of print]
    Endoplasmic reticulum-associated degradation controls virus protein homeostasis that is required for the flavivirus propagation.
    Keisuke Tabata, Masashi Arakawa, Kotaro Ishida, Makiko Kobayashi, Atsuki Nara, Takehiro Sugimoto, Tetsuya Okada, Kazutoshi Mori, Eiji Morita.
      Many positive-stranded RNA viruses encode polyproteins and viral proteins are generated by processing the polyproteins. This system produces an equal amount of each viral protein, though their required amounts are different. In this study, we found that the extra membrane-anchored non-structural (NS) proteins of Japanese encephalitis virus and dengue virus are rapidly and selectively degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway. Our gene targeting study revealed that ERAD involving Derlin2 and SEL1L, but not Derlin1, is required for the viral genome replication. Derlin2 predominantly localized in the convoluted membrane (CM) of viral replication organelle, and viral NS proteins degraded in the CM. Hence, these results suggest that viral protein homeostasis is regulated by Derlin2-mediated ERAD in the CM, and this process is critical for the propagation of these viruses.ImportanceThe results of this study reveal that the cellular ERAD system controls the amount of each viral protein in virus-infected cells; this "viral protein homeostasis" is critical for viral propagation. Furthermore, we clarified that the "convoluted membrane (CM)," which was previously considered a structure with unknown function, serves as a kind of waste dump where viral protein degradation occurs. We also found that the Derlin2/Sel1L/HRD1-specific pathway is involved in this process, whereas the Derlin1-mediated pathway is not. This novel ERAD-mediated fine-tuning system for the stoichiometries of polyprotein-derived viral proteins may represent a common feature among polyprotein-encoding viruses.
    DOI:  https://doi.org/10.1128/JVI.02234-20
  14. J Cell Biol. 2021 Jul 05. pii: e202006116. [Epub ahead of print]220(7):
    Chromosome oscillation promotes Aurora A-dependent Hec1 phosphorylation and mitotic fidelity.
    Kenji Iemura, Toyoaki Natsume, Kayoko Maehara, Masato T Kanemaki, Kozo Tanaka.
      Most cancer cells show chromosomal instability, a condition where chromosome missegregation occurs frequently. We found that chromosome oscillation, an iterative chromosome motion during metaphase, is attenuated in cancer cell lines. We also found that metaphase phosphorylation of Hec1 at serine 55, which is mainly dependent on Aurora A on the spindle, is reduced in cancer cell lines. The Aurora A-dependent Hec1-S55 phosphorylation level was regulated by the chromosome oscillation amplitude and vice versa: Hec1-S55 and -S69 phosphorylation by Aurora A is required for efficient chromosome oscillation. Furthermore, enhancement of chromosome oscillation reduced the number of erroneous kinetochore-microtubule attachments and chromosome missegregation, whereas inhibition of Aurora A during metaphase increased such errors. We propose that Aurora A-mediated metaphase Hec1-S55 phosphorylation through chromosome oscillation, together with Hec1-S69 phosphorylation, ensures mitotic fidelity by eliminating erroneous kinetochore-microtubule attachments. Attenuated chromosome oscillation and the resulting reduced Hec1-S55 phosphorylation may be a cause of CIN in cancer cell lines.
    DOI:  https://doi.org/10.1083/jcb.202006116
  15. Sci Rep. 2021 May 14. 11(1): 10350
    trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway.
    Yusuke Hirata, Miki Takahashi, Yuto Yamada, Ryosuke Matsui, Aya Inoue, Ryo Ashida, Takuya Noguchi, Atsushi Matsuzawa.
      trans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.
    DOI:  https://doi.org/10.1038/s41598-021-89506-8
  16. Trends Cell Biol. 2021 May 10. pii: S0962-8924(21)00088-X. [Epub ahead of print]
    Principles of membrane remodeling by dynamic ESCRT-III polymers.
    Anna-Katharina Pfitzner, Joachim Moser von Filseck, Aurélien Roux.
      Endosomal protein complex required for transport-III (ESCRT-III) polymers are involved in many crucial cellular functions, from cell division to endosome-lysosome dynamics. As a eukaryotic membrane remodeling machinery, ESCRT-III is unique in its ability to catalyze fission of membrane necks from their luminal side and to participate in membrane remodeling processes of essentially all cellular organelles. Found in Archaea, it is also the most evolutionary ancient membrane remodeling machinery. The simple protein structure shared by all of its subunits assembles into a large variety of filament shapes, limiting our understanding of how these filaments achieve membrane remodeling. Here, we review recent findings that discovered unpredicted properties of ESCRT-III polymers, which enable us to define general principles of the mechanism by which ESCRT-III filaments remodel membranes.
    Keywords:  ESCRT-III; membrane fission; membrane remodeling; molecular mechanism
    DOI:  https://doi.org/10.1016/j.tcb.2021.04.005
  17. Nature. 2021 May 12.
    An aged immune system drives senescence and ageing of solid organs.
    Matthew J Yousefzadeh, Rafael R Flores, Yi Zhu, Zoe C Schmiechen, Robert W Brooks, Christy E Trussoni, Yuxiang Cui, Luise Angelini, Kyoo-A Lee, Sara J McGowan, Adam L Burrack, Dong Wang, Qing Dong, Aiping Lu, Tokio Sano, Ryan D O'Kelly, Collin A McGuckian, Jonathan I Kato, Michael P Bank, Erin A Wade, Smitha P S Pillai, Jenna Klug, Warren C Ladiges, Christin E Burd, Sara E Lewis, Nicholas F LaRusso, Nam V Vo, Yinsheng Wang, Eric E Kelley, Johnny Huard, Ingunn M Stromnes, Paul D Robbins, Laura J Niedernhofer.
      Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
    DOI:  https://doi.org/10.1038/s41586-021-03547-7
  18. Front Pharmacol. 2021 ;12 588063
    Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.
    Lin Cheng.
      Adverse drug reactions are a public health issue that draws widespread attention, especially for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which have high mortality and lack of efficacious treatment. Though T-cell-mediated HLA-interacted immune response has been extensively studied, our understanding of the mechanism is far from satisfactory. This review summarizes infection (virus, bacterial, and mycoplasma infection), an environmental risk factor, as a trigger for SJS/TEN. The mutations or polymorphisms of drug metabolic enzymes, transporters, receptors, the immune system genes, and T-cell-mediated apoptosis signaling pathways that contribute to SJS/TEN are discussed and summarized. Epigenetics, metabolites, and mobilization of regulatory T cells and tolerogenic myeloid precursors are emerged directions to study SJS/TEN. Ex vivo lymphocyte transformation test has been exploited to aid in identifying the causative drugs. Critical questions on the pathogenesis of SJS/TEN underlying gene polymorphisms and T cell cytotoxicity remain: why some of the patients carrying the risky genes tolerate the drug and do not develop SJS/TEN? What makes the skin and mucous membrane so special to be targeted? Do they relate to skin/mucous expression of transporters? What is the common machinery underlying different HLA-B alleles associated with SJS/TEN and common metabolites?
    Keywords:  HLA; Stevens-Johnson syndrome; pathogenesis; pharmacogenetics; toxic epidermal necrolysis
    DOI:  https://doi.org/10.3389/fphar.2021.588063
  19. Ann Transl Med. 2021 Apr;9(8): 636
    Diabetic nephropathy in mice is aggravated by the absence of podocyte IRE1 and is correlated with reduced kidney ADH1 expression.
    Liping Xie, Kaifeng Guo, Sijia Lu, Ning Wang, Yanping Wang, Haibing Chen, Junli Liu, Weiping Jia.
      Background: Inositol-requiring enzyme 1 (IRE1) plays a critical role in attenuating endoplasmic reticulum (ER) stress associated with renal injury which may also be a factor in diabetic nephropathy (DN). Alcohol dehydrogenase type I (ADH1) activity is prominent in the kidney, ADH1 activity is also reported to exert protective effects against ER stress that are not caused by alcohol consumption. However, the role of IRE1 in DN and the correlation between IRE1 and ADH1 activity remain unclear.Methods: IRE1α floxed mice (Ire1f/f ) of C57BL/6J background were established and crossbred with Ire1αf/f mice to produce podocyte-specific IRE1α knockout mice. Male db/db mice (C57BLKS/J-leprdb/leprdb mice) were used as a DN model. Male mice were made diabetic by injection of streptozotocin. pLKO.1-based vectors encoding short hairpin RNA (shRNA) specific to the IRE1α gene were transfected into HEK293T cells to knockdown IRE1α in mouse podocytes. ELISA, Masson's staining, and electron microscopy were performed to analyze the development of DN. The ADH1 expression was assayed by qPCR and western blot.
    Results: We found that IRE activity was increased in the glomeruli of DN mouse models. In contrast, ADH1 expression was decreased in these models and mice with podocyte-specific disruption of IRE1 (PKO mice). PKO mice that were made diabetic using strepto-zotocin exhibited accelerated proteinuria, enhanced glomerular fibrosis, and podocyte cell death. In addition, in cultured podocytes, the knockdown of IRE1 downregulated the ADH1 mRNA expression and induced ER stress, consistent with the result of PKO mice, while its detrimental effects were reversed by ADH1 overexpression.
    Conclusions: Activation of IRE1 in podocytes serves to limit the progress of DN. The dependence of kidney ADH1 expression on podocyte IRE1 further suggests that ADH1 activity may play an important role downstream of IRE1 in protecting against DN.
    Keywords:  Inositol-requiring enzyme 1 (IRE1); albuminuria; alcohol dehydrogenase type I (ADH1); diabetic nephropathy (DN); podocyte
    DOI:  https://doi.org/10.21037/atm-20-6356
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:19:42.