bims-unfpre 2024-02-25 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–02–25
ten papers selected by
Susan Logue, University of Manitoba

IRE1 RNase controls CD95-mediated cell death.
IP3R2-mediated Ca2+ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway.
Endoplasmic reticulum stress and the unfolded protein response: emerging regulators in progression of traumatic brain injury.
Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability.
ER stress and unfolded protein response (UPR) signaling modulate GLP-1 receptor signaling in the pancreatic islets.
HRD1-induced TMEM2 ubiquitination promotes ER stress-mediated apoptosis through a non-canonical pathway in intestinal ischemia/reperfusion.
Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy.
Construction of molecular subtype model of osteosarcoma based on endoplasmic reticulum stress and tumor metastasis-related genes.
Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.
ER remodeling via lipid metabolism.

EMBO Rep. 2024 Feb 21.

IRE1 RNase controls CD95-mediated cell death.

Diana Pelizzari-Raymundo, Victoria Maltret, Manon Nivet, Raphael Pineau, Alexandra Papaioannou, Xingchen Zhou, Flavie Caradec, Sophie Martin, Matthieu Le Gallo, Tony Avril, Eric Chevet, Elodie Lafont.

  Signalling by the Unfolded Protein Response (UPR) or by the Death Receptors (DR) are frequently activated towards pro-tumoral outputs in cancer. Herein, we demonstrate that the UPR sensor IRE1 controls the expression of the DR CD95/Fas, and its cell death-inducing ability. Both genetic and pharmacologic blunting of IRE1 activity increased CD95 expression and exacerbated CD95L-induced cell death in glioblastoma (GB) and Triple-Negative Breast Cancer (TNBC) cell lines. In accordance, CD95 mRNA was identified as a target of Regulated IRE1-Dependent Decay of RNA (RIDD). Whilst CD95 expression is elevated in TNBC and GB human tumours exhibiting low RIDD activity, it is surprisingly lower in XBP1s-low human tumour samples. We show that IRE1 RNase inhibition limited CD95 expression and reduced CD95-mediated hepatic toxicity in mice. In addition, overexpression of XBP1s increased CD95 expression and sensitized GB and TNBC cells to CD95L-induced cell death. Overall, these results demonstrate the tight IRE1-mediated control of CD95-dependent cell death in a dual manner through both RIDD and XBP1s, and they identify a novel link between IRE1 and CD95 signalling.

Keywords:  CD95; Cell Death; ER Stress; IRE1; Unfolded Protein Response

DOI:  https://doi.org/10.1038/s44319-024-00095-9
Cell Death Discov. 2024 Feb 20. 10(1): 91

IP3R2-mediated Ca2+ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway.

Qing-Rui Wu, Hui Yang, Hui-Dan Zhang, Yong-Jiang Cai, Yan-Xiang Zheng, Heng Fang, Zi-Fan Wang, Su-Juan Kuang, Fang Rao, Huan-Lei Huang, Chun-Yu Deng, Chun-Bo Chen.

Pyroptosis plays a crucial role in sepsis, and the abnormal handling of myocyte calcium (Ca2+) has been associated with cardiomyocyte pyroptosis. Specifically, the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is a Ca2+ release channel in the endoplasmic reticulum (ER). However, the specific role of IP3R2 in sepsis-induced cardiomyopathy (SIC) has not yet been determined. Thus, this study aimed to investigate the underlying mechanism by which IP3R2 channel-mediated Ca2+ signaling contributes to lipopolysaccharide (LPS)-induced cardiac pyroptosis. The SIC model was established in rats by intraperitoneal injection of LPS (10 mg/kg). Cardiac dysfunction was assessed using echocardiography, and the protein expression of relevant signaling pathways was analyzed using ELISA, RT-qPCR, and western blot. Small interfering RNAs (siRNA) and an inhibitor were used to explore the role of IP3R2 in neonatal rat cardiomyocytes (NRCMs) stimulated by LPS in vitro. LPS-induced NLRP3 overexpression and GSDMD-mediated pyroptosis in the rats' heart. Treatment with the NLRP3 inhibitor MCC950 alleviated LPS-induced cardiomyocyte pyroptosis. Furthermore, LPS increased ATP-induced intracellular Ca2+ release and IP3R2 expression in NRCMs. Inhibiting IP3R activity with xestospongin C (XeC) or knocking down IP3R2 reversed LPS-induced intracellular Ca2+ release. Additionally, inhibiting IP3R2 reversed LPS-induced pyroptosis by suppressing the NLRP3/Caspase-1/GSDMD pathway. We also found that ER stress and IP3R2-mediated Ca2+ release mutually regulated each other, contributing to cardiomyocyte pyroptosis. IP3R2 promotes NLRP3-mediated pyroptosis by regulating ER Ca2+ release, and the mutual regulation of IP3R2 and ER stress further promotes LPS-induced pyroptosis in cardiomyocytes.

DOI: https://doi.org/10.1038/s41420-024-01840-8
Cell Death Dis. 2024 Feb 20. 15(2): 156

Endoplasmic reticulum stress and the unfolded protein response: emerging regulators in progression of traumatic brain injury.

Yayi Yang, Dengfeng Lu, Menghan Wang, Guangjie Liu, Yun Feng, Yubo Ren, Xiaoou Sun, Zhouqing Chen, Zhong Wang.

Traumatic brain injury (TBI) is a common trauma with high mortality and disability rates worldwide. However, the current management of this disease is still unsatisfactory. Therefore, it is necessary to investigate the pathophysiological mechanisms of TBI in depth to improve the treatment options. In recent decades, abundant evidence has highlighted the significance of endoplasmic reticulum stress (ERS) in advancing central nervous system (CNS) disorders, including TBI. ERS following TBI leads to the accumulation of unfolded proteins, initiating the unfolded protein response (UPR). Protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6) are the three major pathways of UPR initiation that determine whether a cell survives or dies. This review focuses on the dual effects of ERS on TBI and discusses the underlying mechanisms. It is suggested that ERS may crosstalk with a series of molecular cascade responses, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, autophagy, and cell death, and is thus involved in the progression of secondary injury after TBI. Hence, ERS is a promising candidate for the management of TBI.

DOI: https://doi.org/10.1038/s41419-024-06515-x
Proc Natl Acad Sci U S A. 2024 Feb 27. 121(9): e2322582121

Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability.

Undiagnosed Diseases Network

  Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is one of three pathways that facilitates the translocation of nascent proteins into the ER. The in vivo function of this protein is ill characterized in multicellular organisms. Here, we generated a CRISPR-induced null allele of the fruit fly ortholog CG8320/Tmem208 by replacing the gene with the Kozak-GAL4 sequence. We show that Tmem208 is broadly expressed in flies and that its loss causes lethality, although a few short-lived flies eclose. These animals exhibit wing and eye developmental defects consistent with impaired cell polarity and display mild ER stress. Tmem208 physically interacts with Frizzled (Fz), a planar cell polarity (PCP) receptor, and is required to maintain proper levels of Fz. Moreover, we identified a child with compound heterozygous variants in TMEM208 who presents with developmental delay, skeletal abnormalities, multiple hair whorls, cardiac, and neurological issues, symptoms that are associated with PCP defects in mice and humans. Additionally, fibroblasts of the proband display mild ER stress. Expression of the reference human TMEM208 in flies fully rescues the loss of Tmem208, and the two proband-specific variants fail to rescue, suggesting that they are loss-of-function alleles. In summary, our study uncovers a role of TMEM208 in development, shedding light on its significance in ER homeostasis and cell polarity.

Keywords:  Drosophila; ER stress; PCP; TMEM proteins; hSnd2

DOI:  https://doi.org/10.1073/pnas.2322582121
Mol Cells. 2024 Jan;pii: S1016-8478(23)25254-1. [Epub ahead of print]47(1): 100004

ER stress and unfolded protein response (UPR) signaling modulate GLP-1 receptor signaling in the pancreatic islets.

Yurong Gao, Hanguk Ryu, Hyejin Lee, Young-Joon Kim, Ji-Hye Lee, Jaemin Lee.

  Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by β-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment.

Keywords:  Endoplasmic reticulum stress; G protein-coupled receptor signaling; Glucagon-like peptide-1; Glucagon-like peptide-1 receptor; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.mocell.2023.12.002
Cell Death Dis. 2024 Feb 20. 15(2): 154

HRD1-induced TMEM2 ubiquitination promotes ER stress-mediated apoptosis through a non-canonical pathway in intestinal ischemia/reperfusion.

Xuzi Zhao, Deshun Liu, Yan Zhao, Zhecheng Wang, Yue Wang, Zhao Chen, Shili Ning, Guangzhi Wang, Lu Meng, Jihong Yao, Xiaofeng Tian.

Intestinal ischemia/reperfusion (I/R) injury is a typical pathological course in the clinic with a high morbidity rate. Recent research has pointed out the critical role of ubiquitination during the occurrence and development of intestinal I/R by precisely mediating protein quality control and function. Here, we conducted an integrated multiomic analysis to identify critical ubiquitination-associated molecules in intestinal I/R and identified endoplasmic reticulum-located HRD1 as a candidate molecule. During intestinal I/R, excessive ER stress plays a central role by causing apoptotic pathway activation. In particular, we found that ER stress-mediated apoptosis was mitigated by HRD1 knockdown in intestinal I/R mice. Mechanistically, TMEM2 was identified as a new substrate of HRD1 in intestinal I/R by mass spectrometry analysis, which has a crucial role in attenuating apoptosis and promoting non-canonical ER stress resistance. A strong negative correlation was found between the protein levels of HRD1 and TMEM2 in human intestinal ischemia samples. Specifically, HRD1 interacted with the lysine 42 residue of TMEM2 and reduced its stabilization by K48-linked polyubiquitination. Furthermore, KEGG pathway analysis revealed that TMEM2 regulated ER stress-mediated apoptosis in association with the PI3k/Akt signaling pathway rather than canonical ER stress pathways. In summary, HRD1 regulates ER stress-mediated apoptosis through a non-canonical pathway by ubiquitinating TMEM2 and inhibiting PI3k/Akt activation during intestinal I/R. The current study shows that HRD1 is an intestinal I/R critical regulator and that targeting the HRD1/TMEM2 axis may be a promising therapeutic approach.

DOI: https://doi.org/10.1038/s41419-024-06504-0
ACS Nano. 2024 Feb 21.

Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy.

Zhenzhen Yang, Yulu Teng, Meng Lin, Yiwei Peng, Yitian Du, Qi Sun, Datong Gao, Quan Yuan, Yu Zhou, Yiliang Yang, Jiajia Li, Yanxia Zhou, Xinru Li, Xianrong Qi.

  Cancer progression and treatment-associated cellular stress impairs therapeutic outcome by inducing resistance. Endoplasmic reticulum (ER) stress is responsible for core events. Aberrant activation of stress sensors and their downstream components to disrupt homeostasis have emerged as vital regulators of tumor progression as well as response to cancer therapy. Here, an orchestrated nanophotoinducer (ERsNP) results in specific tumor ER-homing, induces hyperthermia and mounting oxidative stress associated reactive oxygen species (ROS), and provokes intense and lethal ER stress upon near-infrared laser irradiation. The strengthened "dying" of ER stress and ROS subsequently induce apoptosis for both primary and abscopal B16F10 and GL261 tumors, and promote damage-associated molecular patterns to evoke stress-dependent immunogenic cell death effects and release "self-antigens". Thus, there is a cascade to activate maturation of dendritic cells, reprogram myeloid-derived suppressor cells to manipulate immunosuppression, and recruit cytotoxic T lymphocytes and effective antitumor response. The long-term protection against tumor recurrence is realized through cascaded combinatorial preoperative and postoperative photoimmunotherapy including the chemokine (C-C motif) receptor 2 antagonist, ERsNP upon laser irradiation, and an immune checkpoint inhibitor. The results highlight great promise of the orchestrated nanophotoinducer to exert potent immunogenic cell stress and death by reinforcing ER stress and oxidative stress to boost cancer photoimmunotherapy.

Keywords:  combinatorial photoimmunotherapy; endoplasmic reticulum stress; immunogenic cell stress and death; immunosuppressive myeloid-derived suppressor cells; oxidative stress

DOI:  https://doi.org/10.1021/acsnano.3c13143
Heliyon. 2024 Feb 15. 10(3): e25691

Construction of molecular subtype model of osteosarcoma based on endoplasmic reticulum stress and tumor metastasis-related genes.

Wang-Qiang Wu, Cheng-Da Zou, Di Wu, Hou-Xin Fu, Xiao-Dong Wang, Feng Yao.

   Introduction: Osteosarcoma, the prevailing primary bone malignancy among children and adolescents, is frequently associated with treatment failure primarily due to its pronounced metastatic nature.
Methods: This study aimed to establish potential associations between hub genes and subtypes for the treatment of metastatic osteosarcoma. Differentially expressed genes were extracted from patients diagnosed with metastatic osteosarcoma and a control group of non-metastatic patients, using the publicly available gene expression profile (GSE21257). The intersection of these gene sets was determined by focusing on endoplasmic reticulum (ER) stress-related genes sourced from the GeneCards database. We conducted various analytical techniques, including functional and pathway enrichment analysis, WGCNA analysis, protein-protein interaction (PPI) network construction, and assessment of immune cell infiltration, using the intersecting genes. Through this analysis, we identified potential hub genes.
Results: Osteosarcoma subtype models were developed using molecular consensus clustering analysis, followed by an examination of the associations between each subtype and hub genes. A total of 138 potential differentially expressed genes related to endoplasmic reticulum (ER) stress were identified. These genes were further investigated using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) pathways. Additionally, the PPI interaction network revealed 38 interaction relationships among the top ten hub genes. The findings of the analysis revealed a strong correlation between the extent of immune cell infiltration and both osteosarcoma metastasis and the expression of hub genes. Notably, the differential expression of the top ten hub genes was observed in osteosarcoma clusters 1 and 4, signifying their significant association with the disease.
Conclusion: The identification of ten key genes linked to osteosarcoma metastasis and endoplasmic reticulum stress bears potential clinical significance. Additionally, exploring the molecular subtype of osteosarcoma has the capacity to guide clinical treatment decisions, necessitating further investigations and subsequent clinical validations.

Keywords:  Endoplasmic reticulum stress; Metastasis; Osteosarcoma; Subtype analysis

DOI:  https://doi.org/10.1016/j.heliyon.2024.e25691
Nat Commun. 2024 Feb 20. 15(1): 1534

Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.

Sarah Rösing, Fabian Ullrich, Susann Meisterfeld, Franziska Schmidt, Laura Mlitzko, Marijana Croon, Ryan G Nattrass, Nadia Eberl, Julia Mahlberg, Martin Schlee, Anja Wieland, Philipp Simon, Daniel Hilbig, Ulrike Reuner, Alexander Rapp, Julia Bremser, Peter Mirtschink, Stephan Drukewitz, Thomas Zillinger, Stefan Beissert, Katrin Paeschke, Gunther Hartmann, Aleksandra Trifunovic, Eva Bartok, Claudia Günther.

Myotonic dystrophy type 2 (DM2) is a tetranucleotide CCTG repeat expansion disease associated with an increased prevalence of autoimmunity. Here, we identified an elevated type I interferon (IFN) signature in peripheral blood mononuclear cells and primary fibroblasts of DM2 patients as a trigger of chronic immune stimulation. Although RNA-repeat accumulation was prevalent in the cytosol of DM2-patient fibroblasts, type-I IFN release did not depend on innate RNA immune sensors but rather the DNA sensor cGAS and the prevalence of mitochondrial DNA (mtDNA) in the cytoplasm. Sublethal mtDNA release was promoted by a chronic activation of the ATF6 branch of the unfolded protein response (UPR) in reaction to RNA-repeat accumulation and non-AUG translated tetrapeptide expansion proteins. ATF6-dependent mtDNA release and resulting cGAS/STING activation could also be recapitulated in human THP-1 monocytes exposed to chronic endoplasmic reticulum (ER) stress. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic endoplasmic reticulum stress and associated mtDNA leakage. This mtDNA is, in turn, sensed by the cGAS/STING pathway and induces a type-I IFN response predisposing to autoimmunity. Elucidating this pathway reveals new potential therapeutic targets for autoimmune disorders associated with repeat expansion diseases.

DOI: https://doi.org/10.1038/s41467-024-45535-1
Trends Cell Biol. 2024 Feb 22. pii: S0962-8924(24)00023-0. [Epub ahead of print]

ER remodeling via lipid metabolism.

Wonyul Jang, Volker Haucke.

  Unlike most other organelles found in multiple copies, the endoplasmic reticulum (ER) is a unique singular organelle within eukaryotic cells. Despite its continuous membrane structure, encompassing more than half of the cellular endomembrane system, the ER is subdivided into specialized sub-compartments, including morphological, membrane contact site (MCS), and de novo organelle biogenesis domains. In this review, we discuss recent emerging evidence indicating that, in response to nutrient stress, cells undergo a reorganization of these sub-compartmental ER domains through two main mechanisms: non-destructive remodeling of morphological ER domains via regulation of MCS and organelle hitchhiking, and destructive remodeling of specialized domains by ER-phagy. We further highlight and propose a critical role of membrane lipid metabolism in this ER remodeling during starvation.

Keywords:  endoplasmic reticulum; hitchhiking; lipids; membrane contact sites; membrane remodeling; metabolism; nutrient stress

DOI:  https://doi.org/10.1016/j.tcb.2024.01.011