bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒12‒05
seven papers selected by
Susan Logue
University of Manitoba
  1. What's unique? - The unfolded protein response (UPR) in plants.
  2. HRD1-mediated METTL14 degradation regulates m6A mRNA modification to suppress ER proteotoxic liver disease.
  3. Lutein activates downstream signaling pathways of unfolded protein response in hyperglycemic ARPE-19 cells.
  4. ATF6-mediated unfolded protein response facilitates AAV2 transduction by releasing the suppression of AAV receptor on ER stress.
  5. VLX1570 regulates the proliferation and apoptosis of human lung cancer cells through modulating ER stress and the AKT pathway.
  6. Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.
  7. Endoplasmic Reticulum-Mitochondria Contacts: A Potential Therapy Target for Cardiovascular Remodeling-Associated Diseases.
  1. J Exp Bot. 2021 Nov 29. pii: erab513. [Epub ahead of print]
    What's unique? - The unfolded protein response (UPR) in plants.
    Chao-Yuan Yu, Yueh Cho, Oshin Sharma, Kazue Kanehara.
      The investigation of a phenomenon called the unfolded protein response (UPR) started approximately 3 decades ago, and we now know that the UPR is involved in a number of cellular events among metazoans, higher plants, and algae. The relevance of the UPR in human diseases featuring protein folding defects, such as Alzheimer's and Huntington's diseases, has drawn much attention to the response in medical research to date. While metazoans and plants share similar molecular mechanisms of the UPR, recent studies shed light on the uniqueness of the plant UPR, with the plant-specific protein families appearing to play pivotal roles. Given the considerable emphasis on the original discoveries of key factors in metazoans, this mini review aims to highlight the uniqueness of the plant UPR based on recent publications.
    Keywords:  Arabidopsis; DUF538 protein family; IRE1; NAC transcription factor; bZIP60; endoplasmic reticulum (ER) stress; phosphoinositide signaling; stress granule; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1093/jxb/erab513
  2. Mol Cell. 2021 Nov 23. pii: S1097-2765(21)00948-5. [Epub ahead of print]
    HRD1-mediated METTL14 degradation regulates m6A mRNA modification to suppress ER proteotoxic liver disease.
    Juncheng Wei, Bryan T Harada, Dan Lu, Ruihua Ma, Beixue Gao, Yanan Xu, Elena Montauti, Nikita Mani, Shuvam M Chaudhuri, Shana Gregory, Samuel E Weinberg, Donna D Zhang, Richard Green, Chuan He, Deyu Fang.
      Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers an unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here, we discovered that accumulation of unfolded/misfolded proteins selectively induces N6-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes C/EBP-homologous protein (CHOP) mRNA decay through its 3' UTR N6-methyladenosine (m6A) to inhibit its downstream pro-apoptotic target gene expression. UPR induces METTL14 expression by competing against the HRD1-ER-associated degradation (ERAD) machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER-stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA m6A modification pathways, termed the ERm6A pathway, for ER stress adaptation to proteotoxicity.
    DOI:  https://doi.org/10.1016/j.molcel.2021.10.028
  3. Eur J Pharmacol. 2021 Nov 30. pii: S0014-2999(21)00819-0. [Epub ahead of print] 174663
    Lutein activates downstream signaling pathways of unfolded protein response in hyperglycemic ARPE-19 cells.
    Arpitha Haranahalli Shivarudrappa, Kunal Sharan, Ganesan Ponesakki.
      We have earlier demonstrated that lutein effectively prevents hyperglycemia generated sustained oxidative stress in ARPE-19 cells by activating Nrf2 (nuclear factor erythroid 2-related factor 2) signaling. Since evidence portrays an intricate connection between ER (endoplasmic reticulum) stress and hyperglycemia-mediated oxidative stress, we aimed to explore the protective mechanism of lutein on hyperglycemia-induced ER stress in ARPE-19 cells. To determine the effect of lutein, we probed three major downstream branches of unfolded protein response (UPR) signaling pathways using western blot, immunofluorescent and RT-PCR techniques. The data showed a reduction (38%) in protein expression of an imperative ER chaperon, BiP (binding immunoglobulin protein), in glucose-treated ARPE-19 cells. At the same time, lutein pretreatment blocked this glucose-mediated effect, leading to a significant increase in BiP expression. Lutein promoted the phosphorylation of IRE1 (inositol requiring enzyme 1) and subsequent splicing of XBP1 (X-box binding protein 1), leading to enhanced nuclear translocation. Likewise, lutein activated the expression and translocation of transcription factors, ATF6 (activating transcription factor 6) and ATF4 (activating transcription factor 4) suppressed by hyperglycemia. Lutein also increased CHOP (C/EBP-homologous protein) levels in ARPE-19 cultured under high glucose conditions. The mRNA expression study showed that lutein pretreatment upregulates downstream UPR genes HRD1 (ERAD-associated E3 ubiquitin-protein ligase HRD1), p58IPK (protein kinase inhibitor p58) compared to high glucose treatment alone. From our study, it is clear that lutein show protection against hyperglycemia-mediated ER stress in ARPE-19 cells by activating IRE1-XBP1, ATF6, and ATF4 pathways and their downstream activators. Thus, lutein may have the pharmacological potential for protection against widespread disease conditions of ER stress.
    Keywords:  ARPE-19; ER stress; Hyperglycemia; Lutein; UPR pathways
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174663
  4. J Virol. 2021 Dec 01. JVI0110321
    ATF6-mediated unfolded protein response facilitates AAV2 transduction by releasing the suppression of AAV receptor on ER stress.
    Mengtian Cui, Qingfang Zhao, Jing Wang, Yang Si, Shan Cheng, Wei Ding.
      Adeno-associated virus (AAV) is extensively used as a viral vector to deliver therapeutic genes during human gene therapy. A high affinity cellular receptor (AAVR) for most serotypes was recently identified, however, its biological function as a gene product remains unclear. In this study, we used AAVR knockdown cell models to show that AAVR depletion significantly attenuated cells to activate unfolded protein response (UPR) pathways, when exposed to the endoplasmic reticulum (ER) stress inducer, tunicamycin. By analyzing three major UPR pathways, we found that ATF6 signaling was most affected in an AAVR-dependent fashion, distinct to CHOP and XBP1 branches. AAVR capacity in UPR regulation required the full native AAVR protein, and AAV2 capsid binding to the receptor altered ATF6 dynamics. Conversely, the transduction efficiency of AAV2 was associated with changes in ATF6 signaling in host cells following treatment with different small molecules. Thus, AAVR served as an inhibitory molecule to repress UPR responses via a specificity for ATF6 signaling, and the AAV2 infection route involved the release from AAVR-mediated ATF6 repression, thereby facilitating viral intracellular trafficking and transduction. Importance The native function of the AAVR as an ER-Golgi localized protein is largely unknown. We showed that AAVR acted as a functional molecule to regulate UPR signaling under induced ER stress. AAVR inhibited the activation of the transcription factor, ATF6, whereas receptor binding to AAV2 released the suppression effects. This finding has expanded our understanding of AAV infection biology in terms of the physiological properties of AAVR in host cells. Importantly, our research provides a possible strategy which may improve the efficiency of AAV mediated gene delivery during gene therapy.
    DOI:  https://doi.org/10.1128/JVI.01103-21
  5. J Cell Mol Med. 2021 Dec 01.
    VLX1570 regulates the proliferation and apoptosis of human lung cancer cells through modulating ER stress and the AKT pathway.
    Juan Wang, Tongde Du, Ya Lu, Yan Lv, Yuxin Du, Jianzhong Wu, Rong Ma, Chenxin Xu, Jifeng Feng.
      The ubiquitin-proteasome system (UPS) possesses unique functions in tumorigenesis and has great potential for targeting tumours. The effectiveness of inhibitors targeting UPS in solid tumours remains to be studied. We screened a library of inhibitors targeting the ubiquitination system and found the highly potent, low-concentration inhibitor molecule VLX1570 that specifically killed lung cancer cells. VLX1570 is an inhibitor of deubiquitinating enzyme activity and has also shown potential for preclinical cancer treatment. We found that VLX1570 significantly inhibited lung cancer cells proliferation and colony formation. VLX1570 induced a G2/M cell cycle arrest by downregulating CDK1 and CyclinB1. Moreover, VLX1570 significantly promoted the mitochondrial-associated apoptosis. Mechanistically speaking, VLX1570 activated the PERK/IRE1/ATF6 pathway and induced ER stress in lung cancer cell lines. The inhibition of ER stress by tauroursodeoxycholic acid sodium or 4-phenylbutyric acid enhanced VLX1570-induced apoptosis. In addition, VLX1570 treatment led to the inactivation of Akt signalling and inhibited the proliferation of lung cancer cells by downregulating the Akt pathway. Moreover, combined treatment with VLX1570 and Afatinib or Gefitinib induced synergistic anti-lung cancer activity. Our present study demonstrated a novel therapy using VLX1570, which inhibited the proliferation and increased apoptosis in human lung cancer.
    Keywords:  AKT pathway; ER stress; VLX1570; apoptosis; lung cancer; proliferation
    DOI:  https://doi.org/10.1111/jcmm.17053
  6. J Cell Sci. 2021 Dec 02. pii: jcs.259254. [Epub ahead of print]
    Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.
    Imadeddin Hijazi, Emily Wang, Michelle Orozco, Sarah Pelton, Amy Chang.
      Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.
    Keywords:  Endoplasmic reticulum; Mitochondria; Stress survival
    DOI:  https://doi.org/10.1242/jcs.259254
  7. Front Cell Dev Biol. 2021 ;9 774989
    Endoplasmic Reticulum-Mitochondria Contacts: A Potential Therapy Target for Cardiovascular Remodeling-Associated Diseases.
    Yu Wang, Xinrong Zhang, Ya Wen, Sixuan Li, Xiaohui Lu, Ran Xu, Chao Li.
      Cardiovascular remodeling occurs in cardiomyocytes, collagen meshes, and vascular beds in the progress of cardiac insufficiency caused by a variety of cardiac diseases such as chronic ischemic heart disease, chronic overload heart disease, myocarditis, and myocardial infarction. The morphological changes that occur as a result of remodeling are the critical pathological basis for the occurrence and development of serious diseases and also determine morbidity and mortality. Therefore, the inhibition of remodeling is an important approach to prevent and treat heart failure and other related diseases. The endoplasmic reticulum (ER) and mitochondria are tightly linked by ER-mitochondria contacts (ERMCs). ERMCs play a vital role in different signaling pathways and provide a satisfactory structural platform for the ER and mitochondria to interact and maintain the normal function of cells, mainly by involving various cellular life processes such as lipid metabolism, calcium homeostasis, mitochondrial function, ER stress, and autophagy. Studies have shown that abnormal ERMCs may promote the occurrence and development of remodeling and participate in the formation of a variety of cardiovascular remodeling-associated diseases. This review focuses on the structure and function of the ERMCs, and the potential mechanism of ERMCs involved in cardiovascular remodeling, indicating that ERMCs may be a potential target for new therapeutic strategies against cardiovascular remodeling-induced diseases.
    Keywords:  calcium transfer; cardiovascular remodeling; endoplasmic reticulum; mitochondria; therapeutic strategies
    DOI:  https://doi.org/10.3389/fcell.2021.774989
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