bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024–02–11
seven papers selected by
Susan Logue, University of Manitoba
  1. Novel insight on IRE1 in the regulation of chondrocyte dedifferentiation through ER stress independent pathway.
  2. Partial limitation of cellular functions and compensatory modulation of unfolded protein response pathways caused by double-knockout of ATF6α and ATF6β.
  3. Recent insights into the effect of endoplasmic reticulum stress in the pathophysiology of intestinal ischaemia‒reperfusion injury.
  4. Rational design of ICD-inducing nanoparticles for cancer immunotherapy.
  5. RACK1 and IRE1 participate in the translational quality control of amyloid precursor protein in Drosophila models of Alzheimer's disease.
  6. Stress Biology: Complexity and Multifariousness in Health and Disease.
  7. Expression and Clinical Significance of IRE1-XBP1s, p62, and Caspase-3 in Colorectal Cancer Patients.
  1. J Physiol Biochem. 2024 Feb 10.
    Novel insight on IRE1 in the regulation of chondrocyte dedifferentiation through ER stress independent pathway.
    Young Seok Eom, Fahad Hassan Shah, Song Ja Kim.
      Inositol-requiring enzyme-1 (IRE1) is the master regulator of the unfolded protein response pathway, associated with the endoplasmic reticulum (ER) in sensing and regulating cell stress. The activity of IRE1 is highly explored and well-characterized in cancer and other cells. However, the IRE1 molecular mechanism in chondrocytes is poorly understood. The present study explored the effect of IRE1 on chondrocytes regarding its chondrogenic gene expression and its correlation with different cellular pathways and cell behavior. Chondrocytes transfected with the cDNA of IRE1 reduced the expression of type II collagen, disrupting chondrocyte differentiation as confirmed by western blotting and immunofluorescence. Upon siRNA treatment, the influence of IRE1 on chondrocyte differentiation is restored by reviving the normal expression of type II collagen. Different molecular pathways were explored to investigate the role of IRE1 in causing chondrocyte dedifferentiation. However, we found no significant correlation, as IRE1 induces dedifferentiation through independent pathways. In response to various endoplasmic reticulum (ER) agonists (2-deoxy-D-glucose), and ER stress antagonists (tauroursodeoxycholic acid and salubrinal), IRE1 overexpression did not affect GRP78/94, as implicated in the pathogenesis of ER stress. Moreover, when IRE1 overexpression was correlated with the inflammation pathway, nuclear factor-kappa B (NFκB), IRE1 substantially increased the expression of p50 while decreasing the expression of nuclear factor kappa light polypeptide alpha (IκBα). These results suggest that IRE1 induces dedifferentiation in chondrocytes by modulating inflammatory pathways that cause dedifferentiation by disrupting type II collagen expression.
    Keywords:  Dedifferentiation; ER stress; Inositol requiring enzyme-1; Nuclear factor-kappa B; Type II collagen
    DOI:  https://doi.org/10.1007/s13105-024-01008-z
  2. Cell Stress Chaperones. 2023 Nov 20. pii: S1355-8145(23)02242-3. [Epub ahead of print]29(1): 34-48
    Partial limitation of cellular functions and compensatory modulation of unfolded protein response pathways caused by double-knockout of ATF6α and ATF6β.
    Ryoko Akai, Hisayo Hamashima, Michiko Saito, Kenji Kohno, Takao Iwawaki.
      Mammalian cells have three types of endoplasmic reticulum (ER) stress-sensing molecules: ATF6, IRE1, and PERK. Among these, ATF6 is unique in that it is processed in an ER-stress-specific manner and functions as a transcription factor for the activation of anti-ER stress genes (such as BiP). ATF6 is known to have two homologues, ATF6α and ATF6β, and a greater understanding of their functions has been achieved through analyses using cultured cells. Physiological functions are also gradually being investigated in mice lacking ATF6α or ATF6β. However, little is known about the effects on mouse organisms of the deletion of both the ATF6α and ATF6β genes, since such double-knockout (DKO) mice suffer embryonic lethality at an early developmental stage. In this study, we generated and analyzed ATF6 DKO mice in which embryonic lethality was evaded by using Cre/loxP technology. Pancreatic β cell-specific ATF6 DKO mice were born normally and lived without dysregulation of blood-glucose levels but had a reduced tolerance to glucose. Islets isolated from ATF6 DKO mice also showed low production and secretion of insulin and mild enhancement of IRE1 and PERK activity. We further examined the developmental abnormalities of systemic ATF6 DKO mice. The phenotypes of ATF6α-/-; ATF6β-/- mice were similar to those previously reported, but ATF6α+/-; ATF6β-/- and ATF6α-/-; ATF6β+/- mice showed embryonic lethality at middle developmental stages, unlike those reported. Analysis of embryonic fibroblasts derived from these mice revealed that ATF6α and ATF6β have a gene-dose-dependent functional redundancy and display distinct differences in their ability to induce BiP expression. (250 words).
    Keywords:  BiP; ER stress; Insulin; Pancreatic β cell
    DOI:  https://doi.org/10.1016/j.cstres.2023.11.002
  3. Biochem Biophys Res Commun. 2024 Feb 01. pii: S0006-291X(24)00147-5. [Epub ahead of print]701 149612
    Recent insights into the effect of endoplasmic reticulum stress in the pathophysiology of intestinal ischaemia‒reperfusion injury.
    Jianmin Zhang, Xiaohui Zhang, Yongqiang Liu, Yajing Shi, Feng Chen, Yufang Leng.
      Intestinal ischaemia‒reperfusion (I/R) injury is a surgical emergency. This condition is associated with a high mortality rate. At present, there are limited number of efficient therapeutic measures for this injury, and the prognosis is poor. Therefore, the pathophysiological mechanisms of intestinal I/R injury must be elucidated to develop a rapid and specific diagnostic and treatment protocol. Numerous studies have indicated the involvement of endoplasmic reticulum (ER) stress in the development of intestinal I/R injury. Specifically, the levels of unfolded and misfolded proteins in the ER lumen are increased due to unfolded protein response. However, persistent ER stress promotes apoptosis of intestinal mucosal epithelial cells through three signalling pathways in the ER, impairing intestinal mucosal barrier function and leading to the dysfunction of intestinal tissues and distant organ compartments. This review summarises the mechanisms of ER stress in intestinal I/R injury, diagnostic indicators, and related treatment strategies with the objective of providing novel insights into future therapies for this condition.
    Keywords:  CHOP; Endoplasmic reticulum stress; GRP78; Intestinal; Ischaemia–reperfusion; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149612
  4. Sci Adv. 2024 Feb 09. 10(6): eadk0716
    Rational design of ICD-inducing nanoparticles for cancer immunotherapy.
    Zhanzhan Zhang, Zheng Pan, Qiushi Li, Qingqing Huang, Linqi Shi, Yang Liu.
      Nanoparticle-based cancer immunotherapy has shown promising therapeutic potential in clinical settings. However, current research mainly uses nanoparticles as delivery vehicles but overlooks their potential to directly modulate immune responses. Inspired by the endogenous endoplasmic reticulum (ER) stress caused by unfolded/misfolded proteins, we present a rationally designed immunogenic cell death (ICD) inducer named NanoICD, which is a nanoparticle engineered for ER targeting and retention. By carefully controlling surface composition and properties, we have obtained NanoICD that can effectively accumulate in the ER, induce ER stress, and activate ICD-associated immune responses. In addition, NanoICD is generally applicable to various proteins and enzymes to further enhance the immunomodulatory capacity, exemplified by encapsulating catalase (CAT) to obtain NanoICD/CAT, effectively alleviated immunosuppressive tumor microenvironment and induced robust antitumor immune responses in 4T1-bearing mice. This work demonstrates engineered nanostructures' potential to autonomously regulate biological processes and provides insights into the development of advanced nanomedicines for cancer treatment.
    DOI:  https://doi.org/10.1126/sciadv.adk0716
  5. J Biol Chem. 2024 Feb 02. pii: S0021-9258(24)00095-4. [Epub ahead of print] 105719
    RACK1 and IRE1 participate in the translational quality control of amyloid precursor protein in Drosophila models of Alzheimer's disease.
    Yu Li, Dongyue Liu, Xuejing Zhang, Suman Rimal, Bingwei Lu, Shuangxi Li.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by dysregulation of the expression and processing of the amyloid precursor protein (APP). Protein quality control systems are dedicated to remove faulty and deleterious proteins to maintain cellular protein homeostasis (proteostasis). Identidying mechanisms underlying APP protein regulation is crucial for understanding AD pathogenesis. However, the factors and associated molecular mechanisms regulating APP protein quality control remain poorly defined. In this study, we show that mutant APP with its mitochondrial-targeting sequence ablated exhibited predominant endoplasmic reticulum (ER) distribution and led to aberrant ER morphology, deficits in locomotor activity, and shortened lifespan. We searched for regulators that could counteract the toxicity caused by the ectopic expression of this mutant APP. Genetic removal of the ribosome-associated quality control (RQC) factor RACK1 resulted in reduced levels of ectopically expressed mutant APP. By contrast, gain of RACK1 function increased mutant APP level. Additionally, overexpression of the ER stress regulator (IRE1) resulted in reduced levels of ectopically expressed mutant APP. Mechanistically, the RQC related ATPase VCP/p97 and the E3 ubiquitin ligase Hrd1 were required for the reduction of mutant APP level by IRE1. These factors also regulated the expression and toxicity of ectopically expressed wild type APP, supporting their relevance to APP biology. Our results reveal functions of RACK1 and IRE1 in regulating the quality control of APP homeostasis and mitigating its pathogenic effects, with implications for the understanding and treatment of AD.
    Keywords:  Drosophila; ER; IRE1; Proteostasis; RACK1; amyloid precursor protein (APP); ribosome-associated quality control (RQC)
    DOI:  https://doi.org/10.1016/j.jbc.2024.105719
  6. Cell Stress Chaperones. 2024 Feb 02. pii: S1355-8145(24)00046-4. [Epub ahead of print]
    Stress Biology: Complexity and Multifariousness in Health and Disease.
    Matthias P Mayer, Laura Blair, Gregory L Blatch, Thiago J Borges, Ahmed Chadli, Gabriela Chiosis, Aurélie de Thonel, Albena Dinkova-Kostova, Heath Ecroyd, Adrienne L Edkins, Takanori Eguchi, Monika Fleshner, Kevin P Foley, Sotirios Fragkostefanakis, Jason Gestwicki, Pierre Goloubinoff, Jennifer A Heritz, Christine M Heske, Jonathan D Hibshman, Jenny Joutsen, Wei Li, Michael Lynes, Marc L Mendillo, Nahid Mivechi, Fortunate Mokoena, Yuka Okusha, Veena Prahlad, Elizabeth Repasky, Sara Sannino, Federica Scalia, Reut Shalgi, Lea Sistonen, Emily Sontag, Patricija van Oosten-Hawle, Anniina Vihervaara, Anushka Wickramaratne, Shawn Xiang Yang Wang, Tawanda Zininga.
      Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response (HSR), unfolded protein response (UPR) and integrated stress response (ISR), that act cell-autonomously in most cells but in multicellular organisms are subjected to cell-nonautonomous regulation. These transcriptional programs downregulate expression of most genes but increase expression of heat shock genes, including genes encoding molecular chaperones and proteases, proteins involved in repair of stress-induced damage to macromolecules and cellular structures. 61 years after the discovery of the heat shock response by Ferruccio Ritossa many aspects of stress biology are still enigmatic. Recent progress in the understanding of stress responses and molecular chaperones was reported at the 12th International Symposium on Heat Shock Proteins in Biology, Medicine and the Environment in the Old Town Alexandria, VA, USA from 28th to 31st of October 2023.
    DOI:  https://doi.org/10.1016/j.cstres.2024.01.006
  7. Iran J Med Sci. 2024 Jan;49(1): 10-21
    Expression and Clinical Significance of IRE1-XBP1s, p62, and Caspase-3 in Colorectal Cancer Patients.
    Mohammadkian Zarafshani, Habibollah Mahmoodzadeh, Vahid Soleimani, Mohammad Amin Moosavi, Marveh Rahmati.
       Background: Three main cell signaling pathways including the endoplasmic reticulum stress (ERS) response, autophagy, and apoptosis play critical roles in both cell survival and death. They were found to crosstalk with one another during tumorigenesis and cancer progression. This study aimed to investigate the expression of the spliced form of X-box binding protein 1 (XBP1s), p62, and caspase-3, as the essential biomarkers of ERS, autophagy, and apoptosis in patients with colorectal cancer (CRC), as well as the correlation between their expression and clinicopathological data.
    Methods: This retrospective study was conducted on formalin-fixed paraffin-embedded (FFPE) blocks, which were collected from patients and their tumor margins, from the tumor bank of Imam Khomeini Hospital (Tehran, Iran) from 2017 to 2019. Tissue microarray (TMA) was used to measure the XBP1s, p62, and caspase-3 biomarkers. Data were analyzed using SPSS software version 20, and P≤0.05 was considered statistically significant.
    Results: Evaluating the total of 91 patients, a significant relationship was found between XBP1s expression and TNM stage (P=0.003), primary tumor (pT) (P=0.054), and the degree of differentiation (P=0.006); and between caspase-3 with pT (P=0.004), and lymphovascular invasion (P=0.02). However, no significant correlation was found between p62 and clinicopathological data. Furthermore, a positive relationship between XBP1s and p62 was confirmed (correlation coefficient: 22.2% and P=0.05).
    Conclusion: Our findings indicated that XBP1s could be considered as a target for therapy in personalized medicine.
    Keywords:   Apoptosis; Autophagy; Caspase-3; Colorectal neoplasm; Endoplasmic reticulum stress
    DOI:  https://doi.org/10.30476/IJMS.2023.96922.2856
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