bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024–12–08
six papers selected by
Susan Logue, University of Manitoba
  1. Opposed regulation of endoplasmic reticulum retention under stress by ERp44 and PDIA6.
  2. The Yin and Yang of hsa-miR-1244 expression levels during activation of the UPR control cell fate.
  3. Chloroquine-induced proinsulin misfolding in the endoplasmic reticulum underlies the attenuation of mature insulin synthesis.
  4. OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice.
  5. Targeting p38 MAPK: A potential bridge between ER stress and age-related bone loss.
  6. Quantitative proteomics reveals the mechanism of endoplasmic reticulum stress-mediated pulmonary fibrosis in mice.
  1. Biochem J. 2024 Dec 02. pii: BCJ20240444. [Epub ahead of print]
    Opposed regulation of endoplasmic reticulum retention under stress by ERp44 and PDIA6.
    Boaz Tirosh, Olaya Yassin, Praveen Bellam, Odai Darawshi, Thomas LaFramboise, Miriam Shmuel, Shakti P Pattanayak, Brian K Law, Maria Hatzoglou.
      Conditions of endoplasmic reticulum (ER) stress reduce protein synthesis by provoking translation regulation, governed by the eIF2α kinase PERK. When PERK is inhibited during ER stress, retention of a selective subset of glycoproteins occurs, a phenomenon we termed selective endoplasmic reticulum retention (sERr). sERr clients are enriched with tyrosine kinase receptors (RTKs), which form large molecular weight disulfide bonded complexes in the ER. The protein disulfide isomerase ERp44 promotes sERr and increases the size of sERr complexes. Here we show that sERr is reversible upon washout. Pulse chase analyses show that upon recovery, only a small fraction of the sERr complexes disintegrates and contributes to the matured proteins, while most are newly synthesized. Sequential inductions of sERr and washouts demonstrate an accelerated recovery that is dependent on the unfolded protein response transducer IRE1. Since IRE1 regulates the expression level PDIA6, we analyzed its contribution to sERr. We found that PDIA6 and ERp44 constitutively interact by disulfides and have opposite effects on resumed recovery of trafficking following removal of sERr conditions. Deletion of ERp44 accelerates, while deletion of PDIA6 slows down recovery with a minimal effect on total protein synthesis. ERp44 is a primary interactor with sERr clients. When missing, PDIA6 partitions more into sERr complexes. Deletion of the tumor suppressor PTEN, which induces RTK signaling, promoted sERr formation kinetics, and accelerated the recovery, suggesting feedback between RTKs signaling and sERr. This study suggests that sERr, should develop physiologically or pathologically, is counteracted by adaptation responses that involve IRE1 and PDIA6.
    Keywords:  ER stress; UPR; disulfides; trafficking
    DOI:  https://doi.org/10.1042/BCJ20240444
  2. Cell Commun Signal. 2024 Dec 02. 22(1): 577
    The Yin and Yang of hsa-miR-1244 expression levels during activation of the UPR control cell fate.
    Paulina Czechowicz, Magdalena Gebert, Sylwia Bartoszewska, Leszek Kalinowski, James F Collawn, Rafal Bartoszewski.
      Regulation of endoplasmic reticulum (ER) homeostasis plays a critical role in maintaining cell survival. When ER stress occurs, a network of three pathways called the unfolded protein response (UPR) is activated to reestablish homeostasis. While it is known that there is cross-talk between these pathways, how this complex network is regulated is not entirely clear. Using human cancer and non-cancer cell lines, two different genome-wide approaches, and two different ER stress models, we searched for miRNAs that were decreased during the UPR and surprisingly found only one, miR-1244, that was found under all these conditions. We also verified that ER-stress related downregulation of miR-1244 expression occurred with 5 different ER stressors and was confirmed in another human cell line (HeLa S3). These analyses demonstrated that the outcome of this reduction during ER stress supported both IRE1 signaling and elevated BIP expression. Further analysis using inhibitors specific for IRE1, ATF6, and PERK also revealed that this miRNA is impacted by all three pathways of the UPR. This is the first example of a complex mechanism by which this miRNA serves as a regulatory check point for all 3 pathways that is switched off during UPR activation. In summary, the results indicate that ER stress reduction of miR-1244 expression contributes to the pro-survival arm of UPR.
    Keywords:  Cell fate decisions; ER stress; UPR; miRNA; microRNA
    DOI:  https://doi.org/10.1186/s12964-024-01967-2
  3. FASEB J. 2024 Dec 15. 38(23): e70201
    Chloroquine-induced proinsulin misfolding in the endoplasmic reticulum underlies the attenuation of mature insulin synthesis.
    Jialu Xu, Ruimin Zhu, Yiyu Chen, Xin Li, Xuequn Chen, Ming Liu, Yumeng Huang.
      Chloroquine (CQ), initially introduced for the clinical treatment of malaria, has subsequently been found to exhibit beneficial effects in combating diabetes mellitus. The anti-hyperglycemic properties of chloroquine may be attributed to its anti-inflammatory response and its ability to activate the insulin signaling pathway. However, both animal and clinical studies have yielded mixed results. Moreover, the impact of chloroquine on pancreatic β-cells, the key player of glycemic control, was not known. To fill this knowledge gap, we investigated the effects of chloroquine on pancreatic β-cell functions. Our findings revealed that while chloroquine did not alter proinsulin expression, it interfered with the conversion of proinsulin to insulin, resulting in reduced insulin levels. Using multiple independent approaches, we further showed that chloroquine disrupted proinsulin oxidative folding in the endoplasmic reticulum (ER) and impaired proinsulin trafficking from ER to Golgi, leading to ER stress and decreased insulin production. Notably, the elevated ER stress observed in chloroquine-treated β-cells was reversed upon knockout of insulin genes, indicating that chloroquine-induced β-cell ER stress primarily through the accumulation of misfolded proinsulin, rather than directly affecting ER homeostasis. Further investigation into the mechanisms underlying chloroquine-induced proinsulin misfolding revealed that the accumulation of misfolded proinsulin was not caused by autophagy inhibition or the alkaline pH of chloroquine. Instead, it was primarily due to the disruption of the interaction between proinsulin and protein disulfide isomerase (PDI). Our findings unveiled new mechanisms of chloroquine treatment and raised important safety considerations regarding the use of chloroquine in diabetes treatment.
    Keywords:  ER stress; chloroquine; insulin synthesis; proinsulin; proinsulin misfolding
    DOI:  https://doi.org/10.1096/fj.202401945R
  4. Nat Commun. 2024 Dec 02. 15(1): 10479
    OSGEP regulates islet β-cell function by modulating proinsulin translation and maintaining ER stress homeostasis in mice.
    Yujie Liu, Xuechun Yang, Jian Zhou, Haijun Yang, Ruimeng Yang, Peng Zhu, Rong Zhou, Tianyuan Wu, Yongchao Gao, Zhi Ye, Xi Li, Rong Liu, Wei Zhang, Honghao Zhou, Qing Li.
      Proinsulin translation and folding is crucial for glucose homeostasis. However, islet β-cell control of Proinsulin translation remains incompletely understood. Here, we identify OSGEP, an enzyme responsible for t6A37 modification of tRNANNU that tunes glucose metabolism in β-cells. Global Osgep deletion causes glucose intolerance, while β-cell-specific deletion induces hyperglycemia and glucose intolerance due to impaired insulin activity. Transcriptomics and proteomics reveal activation of the unfolded protein response (UPR) and apoptosis signaling pathways in Osgep-deficient islets, linked to an increase in misfolded Proinsulin from reduced t6A37 modification. Osgep overexpression in pancreas rescues insulin secretion and mitigates diabetes in high-fat diet mice. Osgep enhances translational fidelity and alleviates UPR signaling, highlighting its potential as a therapeutic target for diabetes. Individuals carrying the C allele at rs74512655, which promotes OSGEP transcription, may show reduced susceptibility to T2DM. These findings show OSGEP is essential for islet β-cells and a potential diabetes therapy target.
    DOI:  https://doi.org/10.1038/s41467-024-54905-8
  5. Cell Signal. 2024 Dec 03. pii: S0898-6568(24)00524-2. [Epub ahead of print] 111549
    Targeting p38 MAPK: A potential bridge between ER stress and age-related bone loss.
    Meng Yin, Xin Zheng, Liang Shi.
      The endoplasmic reticulum (ER) is crucial in the development of numerous age-related bone disorders. Notably, ER stress can precipitate bone loss by orchestrating inflammatory responses, apoptosis, and autophagy through the activation of the p38 MAPK pathway. Age-related bone loss diseases pose a significant burden on society and healthcare as the global population ages. This review provides a comprehensive analysis of recent research advancements, delving into the critical role of ER stress-activated p38 MAPK in inflammation, apoptosis, and autophagy, as well as its impact on bone formation and bone resorption. This review elucidates the molecular mechanisms underlying the involvement of ER stress-activated p38 MAPK in osteoporosis, rheumatoid arthritis, periodontitis, and osteoarthritis and discusses the therapeutic potential of targeting p38 MAPK. Furthermore, this review provides a scientific foundation for new therapeutic strategies by highlighting prospective research directions.
    Keywords:  Age-related bone loss; Endoplasmic reticulum stress; Therapeutic strategies; p38 MAPK
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111549
  6. Heliyon. 2024 Oct 30. 10(20): e39150
    Quantitative proteomics reveals the mechanism of endoplasmic reticulum stress-mediated pulmonary fibrosis in mice.
    Heng Li, Jin Wang, Ziling Li, Zhidong Wu, Yan Zhang, Lingjia Kong, Qingqing Yang, Dong Wang, He Shi, Guozheng Shen, Shuang Zou, Wenqing Zhu, Kaiyuan Fan, Zhongwei Xu.
      Pulmonary fibrosis is a progressive disease that can lead to respiratory failure. Many types of cells are involved in the progression of pulmonary fibrosis. This study utilized quantitative proteomics to investigate the mechanism of TGF-β-induced fibrosis-like changes in mouse epithelial cells. Our findings revealed that TGF-β significantly impacted biological processes related to the endoplasmic reticulum, mitochondrion, and ribonucleoprotein complex. Pull-down assay coupled with proteomics identified 114 proteins that may directly interact with TGF-β, and their functions were related to mitochondria, translation, ubiquitin ligase conjugation, mRNA processing, and actin binding. Among them, 17 molecules were also found in different expression proteins (DEPs) of quantitative proteomic, such as H1F0, MED21, SDF2L1, DAD1, and TMX1. Additionally, TGF-β decreased the folded structure and the number of ribosomes in the endoplasmic reticulum and increased the expression of key proteins in the unfolded protein response, including HRD1, PERK, and ERN1. Overall, our study suggested that TGF-β induced fibrotic changes in mouse lung epithelial cells by ER stress and initiated the unfolded protein response through the PRKCSH/IRE1 and PERK/GADD34/CHOP signaling pathways.
    Keywords:  Alveolar epithelial cell; Endoplasmic reticulum-stress; Fibrosis; TGF-β; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e39150
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