bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023‒02‒19
seven papers selected by
Susan Logue
University of Manitoba
  1. Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes.
  2. Apollo-IRE1: A genetically encoded sensor for live cell and multiplexed imaging of ER stress.
  3. Endoplasmic reticulum stress promotes sepsis-induced muscle atrophy via activation of STAT3 and Smad3.
  4. Apurinic/apyrimidinic endonuclease 1 regulates palmitic acid-mediated apoptosis in cardiomyocytes via endoplasmic reticulum stress.
  5. Mitochondrial recovery by the UPRmt: Insights from C. elegans.
  6. ADSCs-exo attenuates hepatic ischemia-reperfusion injury after hepatectomy by inhibiting endoplasmic reticulum stress and inflammation.
  7. A Year at the Forefront of Proteostasis and Aging.
  1. bioRxiv. 2023 Feb 09. pii: 2023.02.09.527889. [Epub ahead of print]
    Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes.
    Anit Shah, Ian Huck, Kaylia Duncan, Erica R Gansemer, Udayan Apte, Mark A Stamnes, D Thomas Rutkowski.
      In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Several pathways potentially link HNF4α to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4α activity is linked to hepatic ER homeostasis through multiple mechanisms.
    DOI:  https://doi.org/10.1101/2023.02.09.527889
  2. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03272-6. [Epub ahead of print]122(3S1): 436a
    Apollo-IRE1: A genetically encoded sensor for live cell and multiplexed imaging of ER stress.
    Eric J Floro, Jonathan V Rocheleau.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2356
  3. J Cell Physiol. 2023 Feb 15.
    Endoplasmic reticulum stress promotes sepsis-induced muscle atrophy via activation of STAT3 and Smad3.
    Yingfang Zheng, Hongkai Dai, Renyu Chen, Yanxia Zhong, Chenchen Zhou, Yurou Wang, Chengye Zhan, Jinlong Luo.
      Endoplasmic reticulum (ER) stress is involved in skeletal muscle atrophy in various conditions, but the role of ER stress in sepsis-induced muscle atrophy is not well understood. In this study, we conducted experiments in wild-type (WT) mice and C/EBP homologous protein knockout (CHOP KO) mice to explore the role and mechanism of ER stress in sepsis-induced muscle atrophy. Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis. In WT mice, the body weight, muscle mass, and cross-sectional area of muscle fibers in CLP group both decreased significantly compared with sham group, which revealed that sepsis-induced dramatic muscle atrophy. Additionally, sepsis activated the ubiquitin-proteasome system (UPS), accompanied by the activation of ER stress. In vitro, inhibition of ER stress suppressed the activity of E3 ubiquitin ligases and alleviated the myotube atrophy. In vivo, CHOP KO also reduced the expression of E3 ubiquitin ligases and UPS-mediated protein degradation, and significantly attenuated sepsis-induced muscle atrophy. Deletion of CHOP also decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and Smad3, and inhibition of STAT3 and Smad3 partly reduced proteolysis caused by ER stress in vitro. These findings confirm that ER stress activates UPS-mediated proteolysis and promotes sepsis-induced muscle atrophy, which is partly achieved by activating STAT3 and Smad3.
    Keywords:  E3 ubiquitin ligases; STAT3; Smad3; endoplasmic reticulum stress; muscle atrophy; sepsis
    DOI:  https://doi.org/10.1002/jcp.30950
  4. Biochem Biophys Res Commun. 2023 Jan 13. pii: S0006-291X(23)00023-2. [Epub ahead of print]650 123-131
    Apurinic/apyrimidinic endonuclease 1 regulates palmitic acid-mediated apoptosis in cardiomyocytes via endoplasmic reticulum stress.
    Junyu Fan, Manqi Liu, Xiaomin Li, ShengLan Gao, Yahong Wang, Ao Li, Lujun Chen, Dengshuang Zhou, Hongqiao Chen, Zhiliang Xu, Zijun Wu, Keng Wu.
      Cardiomyocyte apoptosis caused by fat metabolism disorder plays an essential role in the pathogenesis of diabetic cardiomyopathy (DCM). Apurinic/apyrimidinic endonuclease 1 (APE1) has multiple functions, including regulating redox and DNA repair. However, the role of APE1 in the pathogenesis of DCM remains unclear. To investigate the mechanism of APE1 on high-fat induced apoptosis in H9C2 cells, we treated H9C2 cells with palmitic acid (PA) as an apoptosis model caused by hyperlipidemia. We found that PA reduced the viability and increased apoptosis of H9C2 cells by inducing up-regulation of APE1 protein and endoplasmic reticulum (ER) stress. APE1 knockdown enhanced PA-induced apoptosis, and ER stress and overexpression of APE1 demonstrated the opposite effect. Furthermore, APE1 regulated PA-induced apoptosis via ER stress. The APE1 mutant (C65A, lack of redox regulation) loses its protective effect against ER stress and apoptosis. These findings indicate that APE1 protects PA-induced H9C2 cardiomyocyte apoptosis through ER stress via its redox-regulated function. This study provided new insights into the therapy for DCM.
    Keywords:  APE1 (apurinic/apyrimidinic endonuclease 1); Apoptosis; Diabetic cardiomyopathy; Endoplasmic reticulum stress; H9C2 cardiomyocytes; Palmitic acid
    DOI:  https://doi.org/10.1016/j.bbrc.2023.01.011
  5. Semin Cell Dev Biol. 2023 Feb 13. pii: S1084-9521(23)00030-7. [Epub ahead of print]
    Mitochondrial recovery by the UPRmt: Insights from C. elegans.
    Joshua D Dodge, Nicholas J Browder, Mark W Pellegrino.
      Mitochondria are multifaceted organelles, with such functions as the production of cellular energy to the regulation of cell death. However, mitochondria incur various sources of damage from the accumulation of reactive oxygen species and DNA mutations that can impact the protein folding environment and impair their function. Since mitochondrial dysfunction is often associated with reductions in organismal fitness and possibly disease, cells must have safeguards in place to protect mitochondrial function and promote recovery during times of stress. The mitochondrial unfolded protein response (UPRmt) is a transcriptional adaptation that promotes mitochondrial repair to aid in cell survival during stress. While the earlier discoveries into the regulation of the UPRmt stemmed from studies using mammalian cell culture, much of our understanding about this stress response has been bestowed to us by the model organism Caenorhabditis elegans. Indeed, the facile but powerful genetics of this relatively simple nematode has uncovered multiple regulators of the UPRmt, as well as several physiological roles of this stress response. In this review, we will summarize these major advancements originating from studies using C. elegans.
    Keywords:  Aging; C. elegans; Host-pathogen interactions; Infection; Mitochondria; Mitochondrial UPR; Stress response
    DOI:  https://doi.org/10.1016/j.semcdb.2023.02.002
  6. J Cell Physiol. 2023 Feb 13.
    ADSCs-exo attenuates hepatic ischemia-reperfusion injury after hepatectomy by inhibiting endoplasmic reticulum stress and inflammation.
    Qianzhen Zhang, Chenxi Piao, Jiayuan Xu, Yue Wang, Tao Liu, Haiyang Ma, Hongbin Wang.
      Hepatic ischemia-reperfusion (I/R) injury commonly occurs during liver surgery. Exosomes from adipose-derived stem cells (ADSCs-exo) induce a hepatoprotective effect during hepatic I/R injury. This study aimed to investigate the possible mechanism by which ADSCs-exo attenuates hepatic I/R injury in rats. Rats were randomly divided into four groups: Sham, I30R + PH, ADSCs, and ADSCs-exo groups. Liver tissues were collected immediately after 24 h of reperfusion for further analyses. The content of inflammatory factors in liver tissue was detected using enzyme-linked immunosorbent assay. The pathological changes in liver tissue were analyzed using HE staining. Transmission electron microscopy was used to visualize the ultrastructural changes of hepatocytes. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect the expression of endoplasmic reticulum stress (ERS)-related genes and proteins. Liver histomorphology and hepatocyte ultrastructure changes improved after ADSCs-exo treatment. Moreover, ADSCs-exo treatment significantly downregulated tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 levels while upregulating IL-10 levels. Western blot analysis suggested that the protein expressions of GRP78, p-PERK, p-eIF2α, p-IRE1α, XBP1s, ATF-6, ATF-4, CHOP, p-JNK, cleaved-Caspase-3, cleaved Caspase-9, and cleaved Caspase-12 significantly decreased after ADSCs-exo treatment. RT-qPCR results demonstrated that mRNA expression of GRP78, IRE1α, XBP1, ATF-6, ATF-4, CHOP, JNK, Caspase-3, Caspase-9, and Caspase-12 markedly reduced after ADSCs-exo treatment. In conclusion, ADSCs-exo protects against hepatic I/R injury after hepatectomy by inhibiting ERS and inflammation. Therefore, ADSCs-exo can be considered as a viable option for the treatment of hepatic I/R injury.
    Keywords:  ADSCs; ERS; exosomes; hepatectomy; inflammation; ischemia-reperfusion
    DOI:  https://doi.org/10.1002/jcp.30968
  7. Biol Open. 2023 Feb 15. pii: bio059750. [Epub ahead of print]12(2):
    A Year at the Forefront of Proteostasis and Aging.
    Maximilian A Thompson, Evandro A De-Souza.
      During aging, animals experience a decline in proteostasis activity, including loss of stress-response activation, culminating in the accumulation of misfolded proteins and toxic aggregates, which are causal in the onset of some chronic diseases. Finding genetic and pharmaceutical treatments that can increase organismal proteostasis and lengthen life is an ongoing goal of current research. The regulation of stress responses by cell non-autonomous mechanisms appears to be a potent way to impact organismal healthspan. In this Review, we cover recent findings in the intersection of proteostasis and aging, with a special focus on articles and preprints published between November 2021 and October 2022. A significant number of papers published during this time increased our understanding of how cells communicate with each other during proteotoxic stress. Finally, we also draw attention to emerging datasets that can be explored to generate new hypotheses that explain age-related proteostasis collapse.
    Keywords:  Cell non-autonomous response; Heat shock response; Longevity; Protein homeostasis; UPR
    DOI:  https://doi.org/10.1242/bio.059750
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