bims-unfpre 2023-10-01 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–10–01
eight papers selected by
Susan Logue, University of Manitoba

IL-1β-pretreated bone mesenchymal stem cell-derived exosomes alleviate septic endoplasmic reticulum stress via regulating SIRT1/ERK pathway.
ER stress: an emerging regulator in GVHD development.
Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review.
Unveiling a differential metabolite modulation of sorghum varieties under increasing tunicamycin-induced endoplasmic reticulum stress.
Signal sequence-triage is activated by translocon obstruction sensed by an ER stress sensor IRE1α.
Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity.
XBP1 promotes NRASG12D pre-B acute lymphoblastic leukaemia through IL-7 receptor signalling and provides a therapeutic vulnerability for oncogenic RAS.
MRPS6 modulates glucose-stimulated insulin secretion in mouse islet cells through mitochondrial unfolded protein response.

Heliyon. 2023 Oct;9(10): e20124

IL-1β-pretreated bone mesenchymal stem cell-derived exosomes alleviate septic endoplasmic reticulum stress via regulating SIRT1/ERK pathway.

Xinsheng Cheng, Shikai Wang, Zhipeng Li, Di He, Jianguo Wu, Weiwei Ding.

   Background: Endoplasmic reticulum (ER) plays a crucial role in the development of organ injury caused by sepsis. Therefore, it is highly important to devise strategies that specially target ER stress for the treatment of sepsis. Previous research has shown that priming chemokines can enhance the therapeutic effects of mesenchymal stem cells (MSCs). In this study, we aimed to investigate the function and mechanism of exosomes derived from MSCs that were pretreated with IL-1β (IB-exos) in the context of septic ER stress.
Methods: Mouse bone MSCs were preconditioned with or without IL-1β and the supernatant was used for exosome extraction. In vitro sepsis cell mode was induced by treating HUVECs with LPS, while in vivo sepsis model was established through cecal ligation and puncture (CLP) operation in mice. Cell viability, apoptosis, motility, and tube formation were assessed using the EDU proliferation assay, flow cytometry analysis, migration assay, and tube formation assay, respectively. The molecular mechanism was investigated using ELISA, qRT-PCR, Western blot, and immunofluorescence staining.
Results: Pretreatment with IL-1β enhanced the positive impact of MSC-exos on the viability, apoptosis, motility, and tube formation ability of HUVECs. The administration of LPS or CLP increased ER stress response, but this effect was blocked by the treatment of IB-exos. Additionally, IB-exos reversed the inhibitory effects of LPS or CLP on the expression levels of SIRT1 and ERK phosphorylation. Knockdown of SIRT1 counteracted the effects of IB-exos on HUVEC cellular function and ER stress. In a mouse model, the injection of IB-exos mitigated sepsis-induced lung injury by inhibiting ER stress response through the activation of SIRT1.
Conclusion: IB-exos have been found to alleviate sepsis-induced lung injury via inhibiting ER stress through the SIRT1/ERK pathway. These findings indicated that IB-exos could potentially be used as a strategy to mitigate lung injury caused by sepsis.

Keywords:  ER stress; Exosomes; Mesenchymal stem cells; SIRT1; Sepsis

DOI:  https://doi.org/10.1016/j.heliyon.2023.e20124
Front Immunol. 2023 ;14 1212215

ER stress: an emerging regulator in GVHD development.

Hee-Jin Choi, Xue-Zhong Yu.

  Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient's cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.

Keywords:  ATF6; ER stress; GVHD; IRE-1; PERK; unfolded protein response (UPR)

DOI:  https://doi.org/10.3389/fimmu.2023.1212215
Int J Mol Sci. 2023 Sep 14. pii: 14066. [Epub ahead of print]24(18):

Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review.

Smriti Shreya, Christophe F Grosset, Buddhi Prakash Jain.

  Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR-IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)-modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets.

Keywords:  endoplasmic reticulum; hepatocellular carcinoma; liver disorders; non-alcoholic fatty liver disease; unfolded protein response

DOI:  https://doi.org/10.3390/ijms241814066
Cell Stress Chaperones. 2023 Sep 29.

Unveiling a differential metabolite modulation of sorghum varieties under increasing tunicamycin-induced endoplasmic reticulum stress.

Francisco Lucas Pacheco Cavalcante, Sávio Justino da Silva, Lineker de Sousa Lopes, Stelamaris de Oliveira Paula-Marinho, Maria Izabel Florindo Guedes, Enéas Gomes-Filho, Humberto Henrique de Carvalho.

  Plants trigger endoplasmic reticulum (ER) pathways to survive stresses, but the assistance of ER in plant tolerance still needs to be explored. Thus, we selected sensitive and tolerant contrasting abiotic stress sorghum varieties to test if they present a degree of tolerance to ER stress. Accordingly, this work evaluated crescent concentrations of tunicamycin (TM µg mL-1): control (0), lower (0.5), mild (1.5), and higher (2.5) on the initial establishment of sorghum seedlings CSF18 and CSF20. ER stress promoted growth and metabolism reductions, mainly in CSF18, from mild to higher TM. The lowest TM increased SbBiP and SbPDI chaperones, as well as SbbZIP60, and SbbIRE1 gene expressions, but mild and higher TM decreased it. However, CSF20 exhibited higher levels of SbBiP and SbbIRE1 transcripts. It corroborated different metabolic profiles among all TM treatments in CSF18 shoots and similarities between profiles of mild and higher TM in CSF18 roots. Conversely, TM profiles of both shoots and roots of CSF20 overlapped, although it was not complete under low TM treatment. Furthermore, ER stress induced an increase of carbohydrates (dihydroxyacetone in shoots, and cellobiose, maltose, ribose, and sucrose in roots), and organic acids (pyruvic acid in shoots, and butyric and succinic acids in roots) in CSF20, which exhibited a higher degree of ER stress tolerance compared to CSF18 with the root being the most affected plant tissue. Thus, our study provides new insights that may help to understand sorghum tolerance and the ER disturbance as significant contributor for stress adaptation and tolerance engineering.

Keywords:  Cell stress; Chaperones; GC-MS; Metabolic profile; Primary metabolites

DOI:  https://doi.org/10.1007/s12192-023-01382-5
Cell Struct Funct. 2023 Sep 28.

Signal sequence-triage is activated by translocon obstruction sensed by an ER stress sensor IRE1α.

Ashuei Sogawa, Ryota Komori, Kota Yanagitani, Miku Ohfurudono, Akio Tsuru, Koji Kadoi, Yukio Kimata, Hiderou Yoshida, Kenji Kohno.

  Secretory pathway proteins are cotranslationally translocated into the endoplasmic reticulum (ER) of metazoan cells through the protein channel, translocon. Given that there are far fewer translocons than ribosomes in a cell, it is essential that secretory protein-translating ribosomes only occupy translocons transiently. Therefore, if translocons are obstructed by ribosomes stalled or slowed in translational elongation, it possibly results in deleterious consequences to cellular function. Hence, we investigated how translocon clogging by stalled ribosomes affects mammalian cells. First, we constructed ER-destined translational arrest proteins (ER-TAP) as an artificial protein that clogged the translocon in the ER membrane. Here, we show that the translocon clogging by ER-TAP expression activates triage of signal sequences (SS) in which secretory pathway proteins harboring highly efficient SS are preferentially translocated into the ER lumen. Interestingly, the translocon obstructed status specifically activates inositol requiring enzyme 1α (IRE1α) but not protein kinase R-like ER kinase (PERK). Given that the IRE1α-XBP1 pathway mainly induces the translocon components, our discovery implies that lowered availability of translocon activates IRE1α, which induces translocon itself. This results in rebalance between protein influx into the ER and the cellular translocation capacity.Keywords: endoplasmic reticulum, translocation capacity, translocon clogging, IRE1, signal sequence.

Keywords:  IRE1; endoplasmic reticulum; signal sequence; translocation capacity; translocon clogging

DOI:  https://doi.org/10.1247/csf.23072
Cell Commun Signal. 2023 09 25. 21(1): 258

Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity.

Bhavneet Kaur, Pradeep Kumar Sharma, Barun Chatterjee, Bhawana Bissa, Vasugi Nattarayan, Soundhar Ramasamy, Ajay Bhat, Megha Lal, Sarbani Samaddar, Sourav Banerjee, Soumya Sinha Roy.

  Homocysteine (Hcy), produced physiologically in all cells, is an intermediate metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) resulting from an in-born error of metabolism that leads to accumulation of high levels of Hcy, is associated with vascular damage, neurodegeneration and cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced neurotoxicity associated with mitochondrial dysfunction, fragmentation and apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced proteotoxicity leading to ER stress. We show this sustained proteotoxicity originates from the perturbation of upstream autophagic pathways through an aberrant activation of mTOR and that protetoxic stress act as a feedforward cues to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also rescue neuronal lethality by activation of autophagy and thereby reducing proteotoxicity and ER stress. Our findings pave the way to devise new strategies for the treatment of neural and cognitive pathologies reported in HHcy, by either activation of upstream autophagy or by suppression of downstream ER stress. Video Abstract.

Keywords:  Apoptosis; Autophagy; CBS; Endoplasmic reticulum; Homocysteine; Hyperhomocysteinemia; Mitochondria; Neuron

DOI:  https://doi.org/10.1186/s12964-023-01288-w
J Cell Mol Med. 2023 Sep 27.

XBP1 promotes NRASG12D pre-B acute lymphoblastic leukaemia through IL-7 receptor signalling and provides a therapeutic vulnerability for oncogenic RAS.

Azam Salimi, Mirle Schemionek-Reinders, Michael Huber, Margherita Vieri, John B Patterson, Julia Alten, Tim H Brümmendorf, Behzad Kharabi Masouleh, Iris Appelmann.

  Activating point mutations of the RAS gene act as driver mutations for a subset of precursor-B cell acute lymphoblastic leukaemias (pre-B ALL) and represent an ambitious target for therapeutic approaches. The X box-binding protein 1 (XBP1), a key regulator of the unfolded protein response (UPR), is critical for pre-B ALL cell survival, and high expression of XBP1 confers poor prognosis in ALL patients. However, the mechanism of XBP1 activation has not yet been elucidated in RAS mutated pre-B ALL. Here, we demonstrate that XBP1 acts as a downstream linchpin of the IL-7 receptor signalling pathway and that pharmacological inhibition or genetic ablation of XBP1 selectively abrogates IL-7 receptor signalling via inhibition of its downstream effectors, JAK1 and STAT5. We show that XBP1 supports malignant cell growth of pre-B NRASG12D ALL cells and that genetic loss of XBP1 consequently leads to cell cycle arrest and apoptosis. Our findings reveal that active XBP1 prevents the cytotoxic effects of a dual PI3K/mTOR pathway inhibitor (BEZ235) in pre-B NRASG12D ALL cells. This implies targeting XBP1 in combination with BEZ235 as a promising new targeted strategy against the oncogenic RAS in NRASG12D -mutated pre-B ALL.

Keywords:  IL-7; NRASG12D; PI3K/mTOR; XBP1; acute lymphoblastic leukaemia

DOI:  https://doi.org/10.1111/jcmm.17904
Sci Rep. 2023 09 27. 13(1): 16173

MRPS6 modulates glucose-stimulated insulin secretion in mouse islet cells through mitochondrial unfolded protein response.

Danhong Lin, Jingwen Yu, Leweihua Lin, Qianying Ou, Huibiao Quan.

Lack of efficient insulin secretion from the pancreas can lead to impaired glucose tolerance (IGT), prediabetes, and diabetes. We have previously identified two IGT-associated single nucleotide polymorphisms (SNPs) rs62212118 and rs13052524 located at two overlapping genes: MRPS6 and SLC5A3. In this study, we show that MRPS6 but not SLC5A3 regulates glucose-stimulated insulin secretion (GSIS) in primary human β-cell and a mouse pancreatic insulinoma β-cell line. Data mining and biochemical studies reveal that MRPS6 is positively regulated by the mitochondrial unfolded protein response (UPRmt), but feedback inhibits UPRmt. Disruption of such feedback by MRPS6 knockdown causes UPRmt hyperactivation in high glucose conditions, hence elevated ROS levels, increased apoptosis, and impaired GSIS. Conversely, MRPS6 overexpression reduces UPRmt, mitigates high glucose-induced ROS levels and apoptosis, and enhances GSIS in an ATF5-dependent manner. Consistently, UPRmt up-regulation or down-regulation by modulating ATF5 expression is sufficient to decrease or increase GSIS. The negative role of UPRmt in GSIS is further supported by analysis of public transcriptomic data from murine islets. In all, our studies identify MRPS6 and UPRmt as novel modulators of GSIS and apoptosis in β-cells, contributing to our understanding of the molecular and cellular mechanisms of IGT, prediabetes, and diabetes.

DOI: https://doi.org/10.1038/s41598-023-43438-7