bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024–09–01
eight papers selected by
Susan Logue, University of Manitoba
  1. Endoplasmic reticulum stress in diseases.
  2. Angiogenic factor induced by ER stress promotes tissue repair after myocardial infarction.
  3. Endoplasmic Reticulum Stress Differently Modulates the Release of IL-6 and IL-8 Cytokines in Human Glial Cells.
  4. TRPA1 aggravates osteoclastogenesis and osteoporosis through activating endoplasmic reticulum stress mediated by SRXN1.
  5. Bacterial amyloid curli activates the host unfolded protein response via IRE1α in the presence of HLA-B27.
  6. ATF family members as therapeutic targets in cancer: From mechanisms to pharmacological interventions.
  7. Impaired unfolded protein response drives pathogenic T cell activation in HFpEF.
  8. Endoplasmic Reticulum Stress-Mediated Cell Death in Renal Fibrosis.
  1. MedComm (2020). 2024 Sep;5(9): e701
    Endoplasmic reticulum stress in diseases.
    Yingying Liu, Chunling Xu, Renjun Gu, Ruiqin Han, Ziyu Li, Xianrong Xu.
      The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.
    Keywords:  diseases; endoplasmic reticulum stress (ER stress); therapeutic strategies ; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1002/mco2.701
  2. Nat Cardiovasc Res. 2024 Feb;3(2): 108-109
    Angiogenic factor induced by ER stress promotes tissue repair after myocardial infarction.
      
    DOI:  https://doi.org/10.1038/s44161-024-00430-2
  3. Int J Mol Sci. 2024 Aug 09. pii: 8687. [Epub ahead of print]25(16):
    Endoplasmic Reticulum Stress Differently Modulates the Release of IL-6 and IL-8 Cytokines in Human Glial Cells.
    Paulina Sokołowska, Anna Wiktorowska-Owczarek, Jakub Tambor, Sebastian Gawlak-Socka, Edward Kowalczyk, Marta Jóźwiak-Bębenista.
      Endoplasmic reticulum (ER) stress is a significant player in the pathophysiology of various neurodegenerative and neuropsychiatric disorders. Despite the established link between ER stress and inflammatory pathways, there remains a need for deeper exploration of the specific cellular mechanisms underlying ER stress-mediated neuroinflammation. This study aimed to investigate how the severity of ER stress (triggered by different concentrations of tunicamycin) can impact the release of proinflammatory cytokines IL-6 and IL-8 from astrocytes and microglia, comparing the effects with those induced by well-known immunostimulants-tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). Mild ER stress has a distinct effect on the cytokine release compared to more intense stress levels, i.e., diminished IL-6 production was accompanied by an increase in IL-8 level, which was significantly more pronounced in astrocytes than in microglia. On the contrary, prolonged or more severe ER stress induced inflammation in glial cells, leading to a time- and concentration-dependent buildup of proinflammatory IL-6, but unlike inflammatory agents, an ER stress inducer diminished IL-8 secretions by glial cells. The differences could hold importance in identifying ER stress markers as potential drug targets for the treatment of neurodegenerative diseases or mood disorders, yet this requires confirmation in more complex animal studies.
    Keywords:  ER stress; astrocytes; microglia; proinflammatory cytokines; tunicamycin
    DOI:  https://doi.org/10.3390/ijms25168687
  4. Cell Death Dis. 2024 Aug 27. 15(8): 624
    TRPA1 aggravates osteoclastogenesis and osteoporosis through activating endoplasmic reticulum stress mediated by SRXN1.
    Pengfei Zhu, Huaqiang Tao, Kai Chen, Miao Chu, Qiufei Wang, Xing Yang, Jun Zhou, Huilin Yang, Dechun Geng.
      Osteoporosis (OP) is a disorder of bone remodeling caused by an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, inhibiting excessive osteoclast activity is one of the promising strategies for treating OP. A major transient receptor potential cation channel, known as transient receptor potential ankyrin 1 (TRPA1), was found to alleviate joint pain and cartilage degeneration in osteoarthritis. However, little research has focused on TRPA1 function in OP. As a result, this study aimed to explore the TRPA1 characteristics and its potential therapeutic function during osteoclastogenesis. The TRPA1 expression gradually increased in the osteoclast differentiation process; however, its suppression with small interfering RNA and an inhibitor (HC030031) significantly controlled the osteoclast count and the expression of osteoclast characteristic genes. Its suppression also inhibited endoplasmic reticulum (ER) stress-related pancreatic ER kinase (PERK) pathways. An ER stress inhibitor (thapsigargin) reversed the down-regulated levels of ER stress and osteoclast differentiation by suppressing TRPA1. Transcriptome sequencing results demonstrated that TRPA1 negatively regulated reactive oxygen species (ROS) and significantly increased the expression of an antioxidant gene, SRXN1. The osteoclast differentiation and the levels of ER stress were enhanced with SRXN1 inhibition. Finally, TRPA1 knockdown targeting macrophages by adeno-associated virus-9 could relieve osteoclast differentiation and osteopenia in ovariectomized mice. In summary, silencing TRPA1 restrained osteoclast differentiation through ROS-mediated down-regulation of ER stress via inhibiting PERK pathways. The study also indicated that TRPA1 might become a prospective treatment target for OP.
    DOI:  https://doi.org/10.1038/s41419-024-07018-5
  5. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2392877
    Bacterial amyloid curli activates the host unfolded protein response via IRE1α in the presence of HLA-B27.
    Kaitlyn Grando, Shingo Bessho, Kayla Harrell, Kathrine Kyrylchuk, Alejandro M Pantoja, Sophia Olubajo, Francisco J Albicoro, Andres Klein-Szanto, Çagla Tükel.
      Salmonella enterica serovar Typhimurium (STm) causes gastroenteritis and can progress to reactive arthritis (ReA). STm forms biofilms in the gut that secrete the amyloid curli, which we previously demonstrated can trigger autoimmunity in mice. HLA-B27 is a genetic risk factor for ReA; activation of the unfolded protein response (UPR) due to HLA-B27 misfolding is thought to play a critical role in ReA pathogenesis. To determine whether curli exacerbates HLA-B27-induced UPR, bone marrow-derived macrophages (BMDMs) isolated from HLA-B27 transgenic (tg) mice were used. BMDMs treated with purified curli exhibited elevated UPR compared to C57BL/6, and curli-induced IL-6 was reduced by pre-treating macrophages with inhibitors of the IRE1α branch of the UPR. In BMDMs, intracellular curli colocalized with GRP78, a regulator of the UPR. In vivo, acute infection with wild-type STm increased UPR markers in the ceca of HLA-B27tg mice compared to C57BL/6. STm biofilms that contain curli were visible in the lumen of cecal tissue sections. Furthermore, curli was associated with macrophages in the lamina propria, colocalizing with GRP78. Together, these results suggest that UPR plays a role in the curli-induced inflammatory response, especially in the presence of HLA-B27, a possible mechanistic link between STm infection and genetic susceptibility to ReA.
    Keywords:  HLA-B27; Salmonella; autoimmunity; curli; reactive arthritis; unfolded protein response
    DOI:  https://doi.org/10.1080/19490976.2024.2392877
  6. Pharmacol Res. 2024 Aug 22. pii: S1043-6618(24)00300-1. [Epub ahead of print]208 107355
    ATF family members as therapeutic targets in cancer: From mechanisms to pharmacological interventions.
    Xueyao Zhang, Zhijia Li, Xiaochun Zhang, Ziyue Yuan, Lan Zhang, Peng Miao.
      The activating transcription factor (ATF)/ cAMP-response element binding protein (CREB) family represents a large group of basic zone leucine zip (bZIP) transcription factors (TFs) with a variety of physiological functions, such as endoplasmic reticulum (ER) stress, amino acid stress, heat stress, oxidative stress, integrated stress response (ISR) and thus inducing cell survival or apoptosis. Interestingly, ATF family has been increasingly implicated in autophagy and ferroptosis in recent years. Thus, the ATF family is important for homeostasis and its dysregulation may promote disease progression including cancer. Current therapeutic approaches to modulate the ATF family include direct modulators, upstream modulators, post-translational modifications (PTMs) modulators. This review summarizes the structural domain and the PTMs feature of the ATF/CREB family and comprehensively explores the molecular regulatory mechanisms. On this basis, their pathways affecting proliferation, metastasis, and drug resistance in various types of cancer cells are sorted out and discussed. We then systematically summarize the status of the therapeutic applications of existing ATF family modulators and finally look forward to the future prospect of clinical applications in the treatment of tumors by modulating the ATF family.
    Keywords:  ATF family; Apoptosis; Autophagy; Cancer; Ferroptosis; Modulators; Stress; Transcription factor
    DOI:  https://doi.org/10.1016/j.phrs.2024.107355
  7. Nat Cardiovasc Res. 2023 Dec;2(12): 1099
    Impaired unfolded protein response drives pathogenic T cell activation in HFpEF.
    Elisa Martini.
      
    DOI:  https://doi.org/10.1038/s44161-023-00400-0
  8. Biomolecules. 2024 Jul 28. pii: 919. [Epub ahead of print]14(8):
    Endoplasmic Reticulum Stress-Mediated Cell Death in Renal Fibrosis.
    Shangze Guo, Yinghao Tong, Ting Li, Kexin Yang, Wei Gao, Fujun Peng, Xiangyu Zou.
      The endoplasmic reticulum (ER) is indispensable for maintaining normal life activities. Dysregulation of the ER function results in the accumulation of harmful proteins and lipids and the disruption of intracellular signaling pathways, leading to cellular dysfunction and eventual death. Protein misfolding within the ER disrupts its delicate balance, resulting in the accumulation of misfolded or unfolded proteins, a condition known as endoplasmic reticulum stress (ERS). Renal fibrosis, characterized by the aberrant proliferation of fibrotic tissue in the renal interstitium, stands as a grave consequence of numerous kidney disorders, precipitating a gradual decline in renal function. Renal fibrosis is a serious complication of many kidney conditions and is characterized by the overgrowth of fibrotic tissue in the glomerular and tubular interstitium, leading to the progressive failure of renal function. Studies have shown that, during the onset and progression of kidney disease, ERS causes various problems in the kidneys, a process that can lead to kidney fibrosis. This article elucidates the underlying intracellular signaling pathways modulated by ERS, delineating its role in triggering diverse forms of cell death. Additionally, it comprehensively explores a spectrum of potential pharmacological agents and molecular interventions aimed at mitigating ERS, thereby charting novel research avenues and therapeutic advancements in the management of renal fibrosis.
    Keywords:  cell death; endoplasmic reticulum stress; renal fibrosis
    DOI:  https://doi.org/10.3390/biom14080919
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