bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒10‒27
eight papers selected by
Susan Logue
University of Manitoba
  1. A guide to assessing Endoplasmic Reticulum homeostasis and stress in mammalian systems.
  2. IRE1 promotes neurodegeneration through autophagy-dependent neuron death in the Drosophila model of Parkinson's disease.
  3. Manganese activates autophagy to alleviate endoplasmic reticulum stress-induced apoptosis via PERK pathway.
  4. EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells.
  5. Regulation of the ER stress response by a mitochondrial microprotein.
  6. Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate.
  7. Salubrinal attenuates nitric oxide mediated PERK:IRE1α: ATF-6 signaling and DNA damage in neuronal cells.
  8. ER stress and Rho kinase activation underlie the vasculopathy of CADASIL.
  1. FEBS J. 2019 Oct 24.
    A guide to assessing Endoplasmic Reticulum homeostasis and stress in mammalian systems.
    Daria Sicari, Agnès Delaunay-Moisan, Laurent Combettes, Eric Chevet, Aeid Igbaria.
      The endoplasmic reticulum (ER) is a multifunctional organelle that constitutes the entry into the secretory pathway. The ER contributes to the maintenance of cellular calcium homeostasis, lipid synthesis and productive secretory and transmembrane protein folding. Physiological, chemical and pathological factors that compromise ER homeostasis lead to ER stress. To cope with this situation, cells activate an adaptive signaling pathway termed the Unfolded Protein Response (UPR) that aims at restoring ER homeostasis. The UPR is transduced through post-translational, translational, post-transcriptional and transcriptional mechanisms initiated by three ER-resident sensors, IRE1□, ATF6□ and PERK. Determining the ins and out of ER homeostasis control and UPR activation still represents a challenge for the community. Hence, standardized criteria and methodologies need to be proposed for monitoring ER homeostasis and ER stress in different model systems. Here, we summarize the pathways that are activated during ER stress and provide approaches aimed at assess ER homeostasis and stress in vitro and in vivo mammalian systems that can be used by researchers to plan and interpret experiments. We recommend the use of multiple assays to verify ER stress because no individual assay is guaranteed to be the most appropriate one.
    Keywords:  Calcium distribution; ER redox state; ER stress; ER structure; UPR
    DOI:  https://doi.org/10.1111/febs.15107
  2. Cell Death Dis. 2019 Oct 22. 10(11): 800
    IRE1 promotes neurodegeneration through autophagy-dependent neuron death in the Drosophila model of Parkinson's disease.
    Cheng Yan, Jingqi Liu, Jiamei Gao, Ying Sun, Lei Zhang, Haiyun Song, Lei Xue, Lixing Zhan, Guanjun Gao, Zunji Ke, Yong Liu, Jingnan Liu.
      Abnormal aggregation of misfolded pathological proteins in neurons is a prominent feature of neurodegenerative disorders including Parkinson's disease (PD). Perturbations of proteostasis at the endoplasmic reticulum (ER) triggers ER stress, activating the unfolded protein response (UPR). Chronic ER stress is thought to underlie the death of neurons during the neurodegenerative progression, but the precise mechanism by which the UPR pathways regulate neuronal cell fate remains incompletely understood. Here we report a critical neurodegenerative role for inositol-requiring enzyme 1 (IRE1), the evolutionarily conserved ER stress sensor, in a Drosophila model of PD. We found that IRE1 was hyperactivated upon accumulation of α-synuclein in the fly photoreceptor neurons. Ectopic overexpression of IRE1 was sufficient to trigger autophagy-dependent neuron death in an XBP1-independent, JNK-dependent manner. Furthermore, IRE1 was able to promote dopaminergic neuron loss, progressive locomotor impairment, and shorter lifespan, whereas blocking IRE1 or ATG7 expression remarkably ameliorated the progression of α-synuclein-caused Parkinson's disease. These results provide in vivo evidence demonstrating that the IRE1 pathway drives PD progression through coupling ER stress to autophagy-dependent neuron death.
    DOI:  https://doi.org/10.1038/s41419-019-2039-6
  3. J Cell Mol Med. 2019 Oct 22.
    Manganese activates autophagy to alleviate endoplasmic reticulum stress-induced apoptosis via PERK pathway.
    Chang Liu, Dong-Ying Yan, Can Wang, Zhuo Ma, Yu Deng, Wei Liu, Bin Xu.
      Overexposure to manganese (Mn) is neurotoxic. Our previous research has demonstrated that the interaction of endoplasmic reticulum (ER) stress and autophagy participates in the early stage of Mn-mediated neurotoxicity in mouse. However, the mechanisms of ER stress signalling pathways in the initiation of autophagy remain confused. In the current study, we first validated that ER stress-mediated cell apoptosis is accompanied by autophagy in SH-SY5Y cells. Then, we found that inhibiting ER stress with 4-phenylbutyrate (4-PBA) decreased ER stress-related protein expression and reduced cell apoptosis, whereas blocking autophagy with 3-methyladenine (3-MA) increased cell apoptosis. These data indicate that protective autophagy was activated to alleviate ER stress-mediated apoptosis. Knockdown of the protein kinase RNA-like ER kinase (PERK) gene inhibited Mn-induced autophagy and weakened the interaction between ATF4 and the LC3 promoter. Our results reveal a novel molecular mechanism in which ER stress may regulate autophagy via the PERK/eIF2α/ATF4 signalling pathway. Additionally, Mn may activate protective autophagy to alleviate ER stress-mediated apoptosis via the PERK/eIF2α/ATF4 signalling pathway in SH-SY5Y cells.
    Keywords:  PERK signalling pathway; autophagy; endoplasmic reticulum stress; manganese; neurotoxicity
    DOI:  https://doi.org/10.1111/jcmm.14732
  4. Cell Death Dis. 2019 Oct 22. 10(11): 801
    EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells.
    Vinay Sagar, Rajita Vatapalli, Barbara Lysy, Sahithi Pamarthy, Jonathan F Anker, Yara Rodriguez, Huiying Han, Kenji Unno, Walter M Stadler, William J Catalona, Maha Hussain, Parkash S Gill, Sarki A Abdulkadir.
      The EPHB4 receptor is implicated in the development of several epithelial tumors and is a promising therapeutic target, including in prostate tumors in which EPHB4 is overexpressed and promotes tumorigenicity. Here, we show that high expression of EPHB4 correlated with poor survival in prostate cancer patients and EPHB4 inhibition induced cell death in both hormone sensitive and castration-resistant prostate cancer cells. EPHB4 inhibition reduced expression of the glucose transporter, GLUT3, impaired glucose uptake, and reduced cellular ATP levels. This was associated with the activation of endoplasmic reticulum stress and tumor cell death with features of immunogenic cell death (ICD), including phosphorylation of eIF2α, increased cell surface calreticulin levels, and release of HMGB1 and ATP. The changes in tumor cell metabolism after EPHB4 inhibition were associated with MYC downregulation, likely mediated by the SRC/p38 MAPK/4EBP1 signaling cascade, known to impair cap-dependent translation. Together, our study indicates a role for EPHB4 inhibition in the induction of immunogenic cell death with implication for prostate cancer therapy.
    DOI:  https://doi.org/10.1038/s41419-019-2042-y
  5. Nat Commun. 2019 Oct 25. 10(1): 4883
    Regulation of the ER stress response by a mitochondrial microprotein.
    Qian Chu, Thomas F Martinez, Sammy Weiser Novak, Cynthia J Donaldson, Dan Tan, Joan M Vaughan, Tina Chang, Jolene K Diedrich, Leo Andrade, Andrew Kim, Tong Zhang, Uri Manor, Alan Saghatelian.
      Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER-mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an undiscovered role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.
    DOI:  https://doi.org/10.1038/s41467-019-12816-z
  6. J Cell Biol. 2019 Oct 23. pii: jcb.201904148. [Epub ahead of print]
    Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate.
    Rachel J Hunt, Lucy Granat, Gregory S McElroy, Ramya Ranganathan, Navdeep S Chandel, Joseph M Bateman.
      Mitochondrial stress contributes to a range of neurological diseases. Mitonuclear signaling pathways triggered by mitochondrial stress remodel cellular physiology and metabolism. How these signaling mechanisms contribute to neuronal dysfunction and disease is poorly understood. We find that mitochondrial stress in neurons activates the transcription factor ATF4 as part of the endoplasmic reticulum unfolded protein response (UPR) in Drosophila We show that ATF4 activation reprograms nuclear gene expression and contributes to neuronal dysfunction. Mitochondrial stress causes an ATF4-dependent increase in the level of the metabolite L-2-hydroxyglutarate (L-2-HG) in the Drosophila brain. Reducing L-2-HG levels directly, by overexpressing L-2-HG dehydrogenase, improves neurological function. Modulation of L-2-HG levels by mitochondrial stress signaling therefore regulates neuronal function.
    DOI:  https://doi.org/10.1083/jcb.201904148
  7. Neurochem Int. 2019 Oct 19. pii: S0197-0186(19)30282-7. [Epub ahead of print] 104581
    Salubrinal attenuates nitric oxide mediated PERK:IRE1α: ATF-6 signaling and DNA damage in neuronal cells.
    Sonam Gupta, Joyshree Biswas, Parul Gupta, Abhishek Singh, Shubhangini Tiwari, Amit Mishra, Sarika Singh.
      The present study was conducted to investigate the effect of salubrinal on nitric oxide mediated endoplasmic reticulum stress signaling and neuronal apoptosis. Rotenone treatment to neuro2a cells caused significantly decreased cell viability, increased cytotoxicity, augmented nitrite levels, increased nitrotyrosine level and augmented level of key ER stress markers (GRP-78, GADD153 and caspase-12). These augmented levels of ER stress markers could be attenuated with pretreatment of nitric oxide synthase inhibitor-aminoguanidine as well as with salubrinal. The rotenone treatment to neuro2a cells also triggered the ER stress induced up regulation of various signaling factors of unfolded protein response involving pPERK, ATF4, p-IRE1α, XBP-1 and ATF-6. Pretreatment of salubrinal significantly attenuated the activation of transmembrane kinases (PERK and IRE1) and ATF6 and restored the rotenone induced altered level of other UPR related signaling factors. Rotenone induced dephosphorylation of eIF2α was also inhibited with salubrinal treatment. Biochemically rotenone treatment to neuro2a cells caused the reactive oxygen species generation, depleted mitochondrial membrane potential and increased intra cellular calcium level which was attenuated with salubrinal treatment. Rotenone treatment to neuro2a cells also caused neuronal apoptosis, DNA fragmentation and chromatin condensation which were attenuated with salubrinal treatment. In conclusion, the findings suggested that rotenone causes the augmented level of nitric oxide which contributes in ER stress and could be inhibited by both aminoguanidine and/or salubrinal treatment. Further, salubrinal treatment attenuates the nitric oxide induced ER stress axis PERK:IRE1α:ATF-6 and inhibits the DNA damage and neuronal apoptosis.
    Keywords:  DNA damage; Endoplasmic reticulum stress; Nitric oxide; Salubrinal
    DOI:  https://doi.org/10.1016/j.neuint.2019.104581
  8. JCI Insight. 2019 Oct 24. pii: 131344. [Epub ahead of print]
    ER stress and Rho kinase activation underlie the vasculopathy of CADASIL.
    Karla B Neves, Adam P Harvey, Fiona Moreton, Augusto C Montezano, Francisco J Rios, Rhéure Alves-Lopes, Aurelie Nguyen Dinh Cat, Paul Rocchiccioli, Christian Delles, Anne Joutel, Keith Muir, Rhian M Touyz.
      CADASIL leads to premature stroke and vascular dementia. Mechanism-specific therapies for this aggressive cerebral small vessel disease are lacking. CADASIL is caused by NOTCH3 mutations that influence vascular smooth muscle cell (VSMC) function through unknown processes. We investigated molecular mechanisms underlying the vasculopathy in CADASIL focusing on ER stress and RhoA/Rho kinase (ROCK). Peripheral small arteries and VSMCs were isolated from gluteal biopsies of CADASIL patients and mesentery of TgNotch3R169C mice (CADASIL model). CADASIL vessels exhibited impaired vasorelaxation, blunted vasoconstriction and hypertrophic remodelling. Expression of NOTCH3 and ER stress target genes was amplified and ER stress response, Rho kinase activity, superoxide production and cytoskeletal-associated protein phosphorylation were increased in CADASIL, processes associated with Nox5 upregulation. Aberrant vascular responses and signalling in CADASIL were ameliorated by inhibitors of Notch3 (gamma-secretase inhibitor), Nox5 (mellitin), ER stress (4-PBA) and ROCK (fasudil). Observations in human CADASIL were recapitulated in TgNotch3R169C mice. These findings indicate that vascular dysfunction in CADASIL involves ER stress/ROCK interplay driven by Notch3-induced Nox5 activation and that NOTCH3 mutation-associated vascular pathology, typical in cerebral vessels, also manifests peripherally. We define Notch3-Nox5/ERstress/ROCK signaling as a novel putative mechanism-specific target and suggest that peripheral artery responses may be an accessible biomarker in CADASIL.
    Keywords:  Signal transduction; Vascular Biology
    DOI:  https://doi.org/10.1172/jci.insight.131344
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