bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–12–25
thirteen papers selected by
Susan Logue, University of Manitoba
  1. Sestrin2 Overexpression Ameliorates Endoplasmic Reticulum Stress-Induced Apoptosis via Inhibiting mTOR Pathway in HepG2 Cells.
  2. The unfolded protein response (UPR) pathway: the unsung hero in breast cancer management.
  3. The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress.
  4. Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation.
  5. LINC00629 protects osteosarcoma cell from ER stress-induced apoptosis and facilitates tumour progression by elevating KLF4 stability.
  6. Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma.
  7. Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.
  8. Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.
  9. miR-1260b inhibits periodontal bone loss by targeting ATF6β mediated regulation of ER stress.
  10. eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model.
  11. Endoplasmic reticulum stress-mediated cell death in liver injury.
  12. Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.
  13. Molecular Mechanism Underlying Role of the XBP1s in Cardiovascular Diseases.
  1. Int J Endocrinol. 2022 ;2022 2009753
    Sestrin2 Overexpression Ameliorates Endoplasmic Reticulum Stress-Induced Apoptosis via Inhibiting mTOR Pathway in HepG2 Cells.
    Huiling Hu, Zhijun Luo, Xiuli Liu, Lisi Huang, Xiaoxia Lu, Rui Ding, Chaohui Duan, Yuqing He.
      Sestrin2 is a highly conserved stress-inducible protein, acting as a crucial part in regulating homeostasis in response to various stress conditions in the cell. However, the role of Sestrin2 in regulating cell apoptosis related to endoplasmic reticulum (ER) has not been fully investigated. Our study presented here aims to reveal the effect of Sestrin2 in tunicamycin (TM)-induced cell apoptosis related to ER stress and its underlying molecular mechanisms. The results demonstrated that Sestrin2 expression was significantly upregulated correlated with ER stress responses in TM treated HepG2 cells. Sestrin2 overexpression obviously alleviated ER stress with the determination of ER stress-related proteins expression. In addition, Sestrin2 overexpression inhibited cell apoptosis with the examination of apoptosis-related proteins and TUNEL assay. However, Sestrin2 knockdown further promoted the ER stress-mediated cell apoptosis. The further mechanistic study revealed that Sestrin2 overexpression inhibited TM-induced mTOR pathway activation. Taken together, our current study indicated that Sestrin2 overexpression ameliorates ER stress-induced apoptosis via inhibiting mTOR pathway in HepG2 cells.
    DOI:  https://doi.org/10.1155/2022/2009753
  2. Apoptosis. 2022 Dec 19.
    The unfolded protein response (UPR) pathway: the unsung hero in breast cancer management.
    Arunita Patra, Arghya Adhikary, Swatilekha Ghosh.
      Tumor cells always have the need to produce an increased amount of proteins in the cells. This elevated amount of proteins increases the pressure on the organelles of the cell such as the endoplasmic reticulum and compels it to increase its protein folding efficiency. However, it is by a matter of fact, that the amount of proteins synthesized outweighs the protein folding capacity of the ER which in turn switches on the UPR pathway by activating the three major molecular sensors and other signaling cascades, which helps in cell survival instead of instant death. However, if this pathway is active for a prolonged period of time the tumor cells heads toward apoptosis. Again, interestingly this is not the same as in case of non- tumorogenic cells. This exhibit a straight natural pathway for tumor cells-specific destruction which has a great implication in today's world where hormone therapies and chemo-therapies are non-effective for various types of breast cancer, a major type being Triple Negative Breast Cancer. Thus a detailed elucidation of the molecular involvement of the UPR pathway in breast cancer may open new avenues for management and attract novel chemotherapeutic targets providing better hopes to patients worldwide.
    Keywords:  Apoptosis; Breast cancer; ER Stress; GRP78; UPR sensors
    DOI:  https://doi.org/10.1007/s10495-022-01803-3
  3. NPJ Precis Oncol. 2022 Dec 21. 6(1): 93
    The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress.
    Udayan Bhattacharya, Elangovan Thavathiru, Fiifi Neizer-Ashun, Chao Xu, Zoran Gatalica, Shailendra Kumar Dhar Dwivedi, Anindya Dey, Priyabrata Mukherjee, Resham Bhattacharya.
      The ubiquitin-specific peptidase 10 (USP10) plays a context-specific, pro or anti-tumorigenic role in different malignancies. However, the role of USP10 in pancreatic cancer remains unclear. Our protein and RNA level analysis from archived specimens and public databases show that USP10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and expression correlates with poor overall patient survival. Phenotypically, silencing USP10 decreased viability, clonal growth and invasive properties of pancreatic cancer cells. Mechanistically, silencing USP10 upregulated BiP and induced endoplasmic reticulum (ER) stress that led to an unfolded protein response (UPR) and upregulation of PERK, IRE1α. Decreased cell viability of USP10 silenced cells could be rescued by a chemical chaperone that promotes protein folding. Our studies suggest that USP10 by protecting pancreatic cancer cells from ER stress may support tumor progression.
    DOI:  https://doi.org/10.1038/s41698-022-00336-x
  4. J Biol Chem. 2022 Dec 20. pii: S0021-9258(22)01264-9. [Epub ahead of print] 102821
    Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation.
    Goonho Park, Ke Xu, Leon Chea, Kyle Kim, Lance Safarta, Keon-Hyoung Song, Jian Wu, Soyoung Park, Hyejung Min, Nobuhiko Hiramatsu, Jaeseok Han, Jonathan H Lin.
      Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms - Unfolded Protein Response (UPR) and Integrated Stress Response (ISR). Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation while inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the ER luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.
    Keywords:  EIF2AK3; ER stress; Integrated Stress Response; Neurodegeneration; PERK; Tau aggregation; Tauopathy; Unfolded Protein Response; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102821
  5. J Exp Clin Cancer Res. 2022 Dec 20. 41(1): 354
    LINC00629 protects osteosarcoma cell from ER stress-induced apoptosis and facilitates tumour progression by elevating KLF4 stability.
    Yuan Wang, Shuo Zheng, Jian Han, Na Li, Renchen Ji, Xiaodong Li, Chuanchun Han, Wenzhi Zhao, Lu Zhang.
       BACKGROUND: Escaping from ER stress-induced apoptosis plays an important role in the progression of many tumours. However, its molecular mechanism in osteosarcoma remains incompletely understood.
    METHODS: The molecular mechanism was investigated using RNA sequencing, qRT-PCR and Western blot assays. The relationship between LINC00629 and KLF4 was investigated using RNA pulldown and ubiquitylation assays. The transcriptional regulation of laminin subunit alpha 4 (LAMA4) by KLF4 was identified using bioinformatic analysis, a luciferase assay, and a chromatin immunoprecipitation assay.
    RESULTS: Here, we demonstrated that LINC00629 was increased under ER stress treatment. Elevated LINC00629 inhibited ER stress-induced osteosarcoma cell apoptosis and promoted clonogenicity and migration in vitro and in vivo. Further mechanistic studies indicated that LINC00629 interacted with KLF4 and suppressed its degradation, which led to a KLF4 increase in osteosarcoma. In addition, we also found that KLF4 upregulated LAMA4 expression by directly binding to its promoter and that LINC00629 inhibited ER stress-induced apoptosis and facilitated osteosarcoma cell clonogenicity and metastasis by activating the KLF4-LAMA4 pathway.
    CONCLUSION: Collectively, our data indicate that LINC00629 is a critical long noncoding RNA (lncRNA) induced by ER stress and plays an oncogenic role in osteosarcoma cell by activating the KLF4-LAMA4 axis.
    Keywords:  KLF4; LAMA4; LINC00629; Osteosarcoma
    DOI:  https://doi.org/10.1186/s13046-022-02569-x
  6. Biomolecules. 2022 Dec 15. pii: 1882. [Epub ahead of print]12(12):
    Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma.
    Peijun Zhu, Ting Li, Qingqing Li, Yawen Gu, Yuan Shu, Kaibo Hu, Leifeng Chen, Xiaogang Peng, Jie Peng, Liang Hao.
      Osteosarcoma is the most common malignant bone tumor, often occurring in children and adolescents. The etiology of most patients is unclear, and the current conventional treatment methods are chemotherapy, radiotherapy, and surgical resection. However, the sensitivity of osteosarcoma to radiotherapy and chemotherapy is low, and the prognosis is poor. The development of new and useful treatment strategies for improving patient survival is an urgent need. It has been found that endoplasmic reticulum (ER) stress (ERS) affects tumor angiogenesis, invasion, etc. By summarizing the literature related to osteosarcoma and ERS, we found that the unfolded protein response (UPR) pathway activated by ERS has a regulatory role in osteosarcoma proliferation, apoptosis, and chemoresistance. In osteosarcoma, the UPR pathway plays an important role by crosstalk with autophagy, oxidative stress, and other pathways. Overall, this article focuses on the relationship between ERS and osteosarcoma and reviews the potential of drugs or gene targets associated with ERS for the treatment of osteosarcoma.
    Keywords:  autophagy; endoplasmic reticulum stress; osteosarcoma; oxidative stress; therapy; unfolded protein response
    DOI:  https://doi.org/10.3390/biom12121882
  7. Int J Mol Sci. 2022 Dec 18. pii: 16162. [Epub ahead of print]23(24):
    Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.
    Hideki Kosako, Yusuke Yamashita, Shuhei Morita, Sadahiro Iwabuchi, Shinichi Hashimoto, Taka-Aki Matsuoka, Takashi Sonoki, Shinobu Tamura.
      Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic β cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma.
    Keywords:  GNF-2; IRE1α; asciminib; c-Abl; multiple myeloma; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms232416162
  8. Am J Pathol. 2022 Dec 16. pii: S0002-9440(22)00397-2. [Epub ahead of print]
    Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.
    Eun-Jin Lee, Monica Sophia Diaz-Aguilar, Hyejung Min, Jihee Choi, Diego Adrian Valdez Duran, Julia M Grandjean, R Luke Wiseman, Heike Kroeger, Jonathan H Lin.
      Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate this question, we analyzed bulk-RNA-seq transcriptomes from retinal-organoids generated from ACHM patients carrying homozygous loss-of-function ATF6 variants. We identified marked dysregulation in mitochondrial respiratory complex gene expression and disrupted mitochondrial morphology in ACHM retinal organoids, indicating that loss of ATF6 leads to previously unappreciated mitochondrial defects in the retina. Next, we compared gene expression from control and ACHM retinal organoids with transcriptome profiles of 7 major retinal cell types generated from recent single-cell transcriptomic maps of non-diseased human retina. Our analysis revealed pronounced down-regulation of cone genes and up-regulation in Müller glia genes, with no significant effects on other retinal cells. Overall, our analysis of ACHM patient retinal organoids identifies new cellular and molecular phenotypes in addition to cone dysfunction: activation of Müller cells, increased ER stress, and disrupted mitochondrial structure and elevated respiratory chain activity gene expression.
    DOI:  https://doi.org/10.1016/j.ajpath.2022.12.002
  9. Front Cell Dev Biol. 2022 ;10 1061216
    miR-1260b inhibits periodontal bone loss by targeting ATF6β mediated regulation of ER stress.
    Chikako Hayashi, Takao Fukuda, Kentaro Kawakami, Masaaki Toyoda, Yuki Nakao, Yukari Watanabe, Takanori Shinjo, Tomomi Sano, Misaki Iwashita, Karen Yotsumoto, Miyu Shida, Takaharu Taketomi, Terukazu Sanui, Takeshi Uchiumi, Takashi Kanematsu, Fusanori Nishimura.
      The expression profiles of exosomal microRNAs (miRNAs) are regulated by the microenvironment, and appropriate priming with mesenchymal stem cells (MSCs) is one of the strategies to enhance the paracrine potency of MSCs. Our previous work demonstrated that exosomes from tumor necrosis factor (TNF)-α-primed human gingiva-derived MSCs (GMSCs) could be a therapeutic tool against periodontitis, and that TNFα-inducible exosomal miR-1260b is essential for the inhibition of alveolar bone loss. However, the precise molecular mechanism underlying miR-1260b-mediated inhibition of osteoclastogenesis is not yet fully understood. Here, we found that the activating transcription factor (ATF)-6β, a novel miR-1260b-targeting gene, is critical for the regulation of osteoclastogenesis under endoplasmic reticulum (ER) stress. An experimental periodontal mouse model demonstrated that induction of ER stress was accompanied by enhanced ATF6β expression, and local administration of miR-1260b and ATF6β siRNA using polyethylenimine nanoparticles (PEI-NPs) significantly suppressed the periodontal bone resorption. In periodontal ligament (PDL) cells, the ER stress inducer, tunicamycin, enhanced the expression of the receptor activator of NF-κB ligand (RANKL), while miR-1260b-mediated downregulation of ATF6β caused RANKL inhibition. Furthermore, the secretome from miR-1260b/ATF6β-axis-activated PDL cells inhibited osteoclastogenesis in human CD14+ peripheral blood-derived monocytes. These results indicate that the miR-1260b/ATF6β axis mediates the regulation of ER stress, which may be used as a novel therapeutic strategy to treat periodontal disease.
    Keywords:  ATF6β; ER stress; GMSCs; miR-1260b; osteoclast; periodontitis
    DOI:  https://doi.org/10.3389/fcell.2022.1061216
  10. Cells. 2022 Dec 15. pii: 4069. [Epub ahead of print]11(24):
    eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model.
    Alina González-Ortiz, Angel Pulido-Capiz, César Y Castañeda-Sánchez, Esmeralda Ibarra-López, Octavio Galindo-Hernández, Maritza Anahí Calderón-Fernández, Leslie Y López-Cossio, Raul Díaz-Molina, Brenda Chimal-Vega, Nicolás Serafín-Higuera, Iván Córdova-Guerrero, Victor García-González.
      Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation initiation could be associated with breast cancer (BC) chemoresistance. Specifically, eukaryotic initiation factor-4A (eIF4A) is involved in the unfolding of the secondary structures of several mRNAs at the 5' untranslated region (5'-UTR), as well as in the regulation of targets involved in chemoresistance. Importantly, the tumor suppressor gene PDCD4 could modulate this process. This regulation might be disrupted in chemoresistant triple negative-BC (TNBC) cells. Therefore, we characterized the effect of doxorubicin (Dox), a commonly used anthracycline medication, on human breast carcinoma MDA-MB-231 cells. Here, we generated and characterized models of Dox chemoresistance, and chemoresistant cells exhibited lower Dox internalization levels followed by alteration of the IRE1 and PERK arms of the UPR and triggering of the antioxidant Nrf2 axis. Critically, chemoresistant cells exhibited PDCD4 downregulation, which coincided with a reduction in eIF4A interaction, suggesting a sophisticated regulation of protein translation. Likewise, Dox-induced chemoresistance was associated with alterations in cellular migration and invasion, which are key cancer hallmarks, coupled with changes in focal adhesion kinase (FAK) activation and secretion of matrix metalloproteinase-9 (MMP-9). Moreover, eIF4A knockdown via siRNA and its overexpression in chemoresistant cells suggested that eIF4A regulates FAK. Pro-atherogenic low-density lipoproteins (LDL) promoted cellular invasion in parental and chemoresistant cells in an MMP-9-dependent manner. Moreover, Dox only inhibited parental cell invasion. Significantly, chemoresistance was modulated by cryptotanshinone (Cry), a natural terpene purified from the roots of Salvia brandegeei. Cry and Dox co-exposure induced chemosensitization, connected with the Cry effect on eIF4A interaction. We further demonstrated the Cry binding capability on eIF4A and in silico assays suggest Cry inhibition on the RNA-processing domain. Therefore, strategic disruption of protein translation initiation is a druggable pathway by natural compounds during chemoresistance in TNBC. However, plasmatic LDL levels should be closely monitored throughout treatment.
    Keywords:  PDCD4; breast cancer; chemoresistance; cryptotanshinone; eIF4A; proteostasis
    DOI:  https://doi.org/10.3390/cells11244069
  11. Cell Death Dis. 2022 Dec 19. 13(12): 1051
    Endoplasmic reticulum stress-mediated cell death in liver injury.
    Jian Zhang, Jiafu Guo, Nannan Yang, Yan Huang, Tingting Hu, Chaolong Rao.
      The endoplasmic reticulum is an important intracellular organelle that plays an important role in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are induced when the body is exposed to adverse external stimuli. It has been established that ERS can induce different cell death modes, including autophagy, apoptosis, ferroptosis, and pyroptosis, through three major transmembrane receptors on the ER membrane, including inositol requirement enzyme 1α, protein kinase-like endoplasmic reticulum kinase and activating transcription factor 6. These different modes of cell death play an important role in the occurrence and development of various diseases, such as neurodegenerative diseases, inflammation, metabolic diseases, and liver injury. As the largest metabolic organ, the liver is rich in enzymes, carries out different functions such as metabolism and secretion, and is the body's main site of protein synthesis. Accordingly, a well-developed endoplasmic reticulum system is present in hepatocytes to help the liver perform its physiological functions. Current evidence suggests that ERS is closely related to different stages of liver injury, and the death of hepatocytes caused by ERS may be key in liver injury. In addition, an increasing body of evidence suggests that modulating ERS has great potential for treating the liver injury. This article provided a comprehensive overview of the relationship between ERS and four types of cell death. Moreover, we discussed the mechanism of ERS and UPR in different liver injuries and their potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-022-05444-x
  12. FEBS J. 2022 Dec 19.
    Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.
    Min Zhang, Xiaoyu Duan, Lu Wang, Jing Wen, Pingfei Fang.
      Mild hypothermia can induce apoptotic cell death in many cancer cells, but the underlying mechanisms remain unclear. In a genetic screen in C. elegans, we found that impaired endoplasmic reticulum unfolded protein response (UPRER ) increased animal survival after cold shock. Consistently, in normal human lung cells, decreasing culture temperature from 37°C to 30°C activated UPRER and promoted cell death. However, lung adenocarcinoma cells were impaired in UPRER induction and resistant to hypothermia-induced cell death. Mechanistically, hypothermic stress increased HSF1 levels, which in turn activated UPRER to promote apoptotic cell death. HSF1 expression was associated with UPRER genes in normal tissues but such association was lost in many cancers, especially lung adenocarcinoma. Activating UPRER enhanced the cytotoxicity of chemotherapy drugs cisplatin preferentially in cancer cells. Consistently, cancer patients with higher UPRER expression had generally better prognosis. Together, our study on hypothermia has led to the discovery of HSF1-UPRER in the regulation of drug sensitivity in lung cancer cells, providing novel thoughts on developing new strategies against chemoresistance.
    Keywords:  HSF1; chemoresistance; hypothermia; lung cancer; unfolded protein response
    DOI:  https://doi.org/10.1111/febs.16709
  13. J Cardiovasc Dev Dis. 2022 Dec 14. pii: 459. [Epub ahead of print]9(12):
    Molecular Mechanism Underlying Role of the XBP1s in Cardiovascular Diseases.
    Shu Liu, Hong Ding, Yongnan Li, Xiaowei Zhang.
      Spliced X-box binding protein-1 (XBP1s) is a protein that belongs to the cAMP-response element-binding (CREB)/activating transcription factor (ATF) b-ZIP family with a basic-region leucine zipper (bZIP). There is mounting evidence to suggest that XBP1s performs a critical function in a range of different cardiovascular diseases (CVDs), indicating that it is necessary to gain a comprehensive knowledge of the processes involved in XBP1s in various disorders to make progress in research and clinical therapy. In this research, we provide a summary of the functions that XBP1s performs in the onset and advancement of CVDs such as atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. Furthermore, we discuss XBP1s as a novel therapeutic target for CVDs.
    Keywords:  cardiac hypertrophy; cardiovascular diseases; heart failure; hypertension; spliced X-box binding protein-1
    DOI:  https://doi.org/10.3390/jcdd9120459
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