bims-unfpre 2023-01-22 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–01–22
eight papers selected by
Susan Logue, University of Manitoba

Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism.
The endoplasmic reticulum stress sensor IRE1α modulates macrophage metabolic function during Brucella abortus infection.
A KO mouse model for the lncRNA Lhx1os produces motor neuron alterations and locomotor impairment.
Tangeretin alleviates Tunicamycin-induced endoplasmic reticulum stress and associated complications in skeletal muscle cells.
Targeting Endoplasmic Reticulum Stress-the Responder to Lipotoxicity and Modulator of Non-Alcoholic Fatty Liver Diseases.
The PTP1B selective inhibitor MSI-1436 mitigates Tunicamycin-induced ER stress in human hepatocarcinoma cell line through XBP1 splicing modulation.
Endoplasmic Reticulum Stress in the Brain Tumor Immune Microenvironment.
The therapeutic mavericks: Potent immunomodulating chaperones capable of treating human diseases.

iScience. 2023 Jan 20. 26(1): 105911

Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism.

Hong Wa Yung, Xiaohui Zhao, Luke Glover, Charlotte Burrin, Poh-Choo Pang, Carolyn J P Jones, Carolyn Gill, Kate Duhig, Matts Olovsson, Lucy C Chappell, Stuart M Haslam, Anne Dell, Graham J Burton, D Stephen Charnock-Jones.

  Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with "protein glycosylation" and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders.

Keywords:  Biological sciences; Human metabolism; Pregnancy

DOI:  https://doi.org/10.1016/j.isci.2022.105911
Front Immunol. 2022 ;13 1063221

The endoplasmic reticulum stress sensor IRE1α modulates macrophage metabolic function during Brucella abortus infection.

Erika S Guimarães, Marco Túlio R Gomes, Rodrigo C O Sanches, Kely Catarine Matteucci, Fábio V Marinho, Sergio C Oliveira.

  Endoplasmic reticulum (ER) stress plays a major role in several inflammatory disorders. ER stress induces the unfolded protein response (UPR), a conserved response broadly associated with innate immunity and cell metabolic function in various scenarios. Brucella abortus, an intracellular pathogen, triggers the UPR via Stimulator of interferon genes (STING), an important regulator of macrophage metabolism during B. abortus infection. However, whether ER stress pathways underlie macrophage metabolic function during B. abortus infection remains to be elucidated. Here, we showed that the UPR sensor inositol-requiring enzyme 1α (IRE1α) is as an important component regulating macrophage immunometabolic function. In B. abortus infection, IRE1α supports the macrophage inflammatory profile, favoring M1-like macrophages. IRE1α drives the macrophage metabolic reprogramming in infected macrophages, contributing to the reduced oxidative phosphorylation and increased glycolysis. This metabolic reprogramming is probably associated with the IRE1α-dependent expression and stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), an important molecule involved in cell metabolism that sustains the inflammatory profile in B. abortus-infected macrophages. Accordingly, we demonstrated that IRE1α favors the generation of mitochondrial reactive oxygen species (mROS) which has been described as an HIF-1α stabilizing factor. Furthermore, in infected macrophages, IRE1α drives the production of nitric oxide and the release of IL-1β. Collectively, these data unravel a key mechanism linking the UPR and the immunometabolic regulation of macrophages in Brucella infection and highlight IRE1α as a central pathway regulating macrophage metabolic function during infectious diseases.

Keywords:  HIF-1α; IRE1α; UPR; brucella abortus; endoplasmic reticulum stress; immunometabolism

DOI:  https://doi.org/10.3389/fimmu.2022.1063221
iScience. 2023 Jan 20. 26(1): 105891

A KO mouse model for the lncRNA Lhx1os produces motor neuron alterations and locomotor impairment.

Flaminia Pellegrini, Vittorio Padovano, Silvia Biscarini, Tiziana Santini, Adriano Setti, Silvia Giulia Galfrè, Valentina Silenzi, Erika Vitiello, Davide Mariani, Carmine Nicoletti, Giulia Torromino, Elvira De Leonibus, Julie Martone, Irene Bozzoni.

  Here, we describe a conserved motor neuron-specific long non-coding RNA, Lhx1os, whose knockout in mice produces motor impairment and postnatal reduction of mature motor neurons (MNs). The ER stress-response pathway result specifically altered with the downregulation of factors involved in the unfolded protein response (UPR). Lhx1os was found to bind the ER-associated PDIA3 disulfide isomerase and to affect the expression of the same set of genes controlled by this protein, indicating that the two factors act in conjunction to modulate the UPR. Altogether, the observed phenotype and function of Lhx1os indicate its important role in the control of MN homeostasis and function.

Keywords:  Behavioral neuroscience; Molecular neuroscience; Neurogenetics

DOI:  https://doi.org/10.1016/j.isci.2022.105891
Cell Stress Chaperones. 2023 Jan 19.

Tangeretin alleviates Tunicamycin-induced endoplasmic reticulum stress and associated complications in skeletal muscle cells.

Eveline M Anto, C R Sruthi, Lekshmy Krishnan, K G Raghu, Jayamurthy Purushothaman.

  Endoplasmic reticulum (ER) stress and associated oxidative stress are involved in the genesis and progression of skeletal muscle diseases such as myositis and atrophy or muscle wasting. Targeting the ER stress and associated downstream pathways can aid in the development of better treatment strategies for these diseases with limited therapeutic approaches. There is a growing interest in identifying natural products against ER stress due to the lower toxicity and cost effectiveness. In the present study, we investigated the protective effect of Tangeretin, a citrus methoxyflavone found in citrus peels against Tunicamycin (pharmacological ER stress inducer)-induced ER stress and associated complications in rat skeletal muscle L6 cell lines. Treatment with Tunicamycin for a period of 24 h resulted in the upregulation of ER stress marker proteins, ER resident oxidoreductases and cellular reactive oxygen species (ROS). Co-treatment with Tangeretin was effective in alleviating Tunicamycin-induced ER stress and associated redox-related complications by significantly downregulating the unfolded protein response (UPR), ER resident oxidoreductase proteins, cellular ROS and improving the antioxidant enzyme activity. Tunicamycin also induced upregulation of phosphorylated p38 MAP Kinase and loss of mitochondrial membrane potential. Tangeretin significantly reduced the levels of phosphorylated p38 MAP Kinase and improved the mitochondrial membrane potential. From the results, it is evident that Tangeretin can be explored further as a potential candidate for skeletal muscle diseases involving protein misfolding and ER stress.

Keywords:  ER stress; L6 cell lines; Oxidative stress; Tangeretin; Tunicamycin

DOI:  https://doi.org/10.1007/s12192-023-01322-3
Expert Opin Ther Targets. 2023 Jan 19.

Targeting Endoplasmic Reticulum Stress-the Responder to Lipotoxicity and Modulator of Non-Alcoholic Fatty Liver Diseases.

Yu Luo, Qiangqiang Jiao, Yuping Chen.

   INTRODUCTION: Endoplasmic reticulum (ER) stress occurs with aberrant lipid accumulation and resultant adverse effects and widely exists in nonalcoholic fatty liver disease (NAFLD). It triggers the unfolded protein response (UPR) to restore ER homeostasis and actively participates in NAFLD pathological processes, including hepatic steatosis, inflammation, hepatocyte death, and fibrosis. Such acknowledges drive the discovery of novel NAFLD biomarker and therapeutic targets and the development of ER-stress targeted NAFLD drugs.
AREAS COVERED: This article discusses and updates the role of ER stress and UPR in NAFLD, the underlying action mechanism, and especially their full participation in NAFLD pathophysiology. It characterizes key molecular targets useful for the prevention and treatment of NAFLD and highlights the recent ER stress-targeted therapeutic strategies for NAFLD.
EXPERT OPINION: Targeting ER Stress is a valuable and promising strategy for NAFLD treatment, but its smooth translation into clinical application still requires better clarification of the different UPR patterns in diverse NAFLD physiological states. Further understanding of the distinct effects of these various patterns on NAFLD, the thresholds deciding their final impacts, and their actions via non-liver tissues and cells would be of great help to develop a precise and effective therapy for NAFLD.

Keywords:  NAFLD; UPR; endoplasmic reticulum stress; hepatic inflammation; steatosis; targeting

DOI:  https://doi.org/10.1080/14728222.2022.2170780
PLoS One. 2023 ;18(1): e0278566

The PTP1B selective inhibitor MSI-1436 mitigates Tunicamycin-induced ER stress in human hepatocarcinoma cell line through XBP1 splicing modulation.

Lynda Bourebaba, Sai Santosh Babu Komakula, Christine Weiss, Nabil Adrar, Krzysztof Marycz.

Protein tyrosine phosphatase PTP1B is considered as a key metabolic enzyme that has been reported to be associated with insulin resistance onset, and underlying cellular metabolic malfunctions, including ER stress and mitochondrial failure. In this study, effects of selective PTP1B inhibition using MSI-1436 on cellular apoptosis, oxidative stress, mitochondrial dysfunction and ER stress have been assessed using an in vitro model of Tunicamycin induced ER stress in HepG2 cell line. Inhibition of PTP1B using MSI-1436 significantly increased cell viability and reduced the number of apoptotic cells as well as the expression of key apoptosis initiators and effectors. MSI-1436 further mitigated ER stress, by downregulating the expression of IRE1, ATF6 and PERK transcripts, all being key ER stress sensors. Interestingly, MSI-1436 inhibited the XBP1 splicing, and thus its UPR-associated transcriptional activity. PTP1B inhibition further enabled to restore proper mitochondrial biogenesis, by improving transmembrane potential, and diminishing intracellular ROS while restoring of endogenous antioxidant enzymes genes expression. PTP1B inhibition using MSI-1436 could improve cellular apoptosis and metabolic integrity through the mitigation of ER and mitochondrial stress signalling pathways, and excessive ROS accumulation. This strategy may be useful for the treatment of metabolic disorders including IR, NAFLD and diabetes.

DOI: https://doi.org/10.1371/journal.pone.0278566
Mol Cancer Res. 2023 Jan 18. pii: MCR-22-0920. [Epub ahead of print]

Endoplasmic Reticulum Stress in the Brain Tumor Immune Microenvironment.

Edgar Petrosyan, Jawad Fares, Luis G Fernandez, Ragini Yeeravalli, Crismita Dmello, Joseph T Duffy, Peng Zhang, Catalina Lee-Chang, Jason Miska, Atique U Ahmed, Adam M Sonabend, Irina V Balyasnikova, Amy B Heimberger, Maciej S Lesniak.

Immunotherapy has emerged as a powerful strategy for halting cancer progression. However, primary malignancies affecting the brain have been exempt to this success. Indeed, brain tumors continue to portend severe morbidity and remain a globally lethal disease. Extensive efforts have been directed at understanding how tumor cells survive and propagate within the unique microenvironment of the central nervous system (CNS). Cancer genetic aberrations and metabolic abnormalities provoke a state of persistent endoplasmic reticulum (ER) stress that in turn promotes tumor growth, invasion, therapeutic resistance, and the dynamic reprogramming of the infiltrating immune cells. Consequently, targeting ER stress is a potential therapeutic approach. In this work, we provide an overview of how ER stress response is advantageous to brain tumor development, discuss the significance of ER stress in governing anti-tumor immunity, and put forth therapeutic strategies of regulating ER stress in order to augment the effect of immunotherapy for primary CNS tumors.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0920
J Cell Mol Med. 2023 Jan 18.

The therapeutic mavericks: Potent immunomodulating chaperones capable of treating human diseases.

Paul Eggleton, Jorge De Alba, Michael Weinreich, Perry Calias, Roly Foulkes, Valerie M Corrigall.

  Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti-inflammatory functions respectively. CRT induces pro-inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti-inflammatory cytokines, inhibits DC maturation and heightens T-regulatory cell responses. These latter functions rebalance immune homeostasis in inflammatory diseases, such as rheumatoid arthritis. Both chaperones are therapeutically relevant agents acting primarily on monocytes/DCs. Endogenous exposure of CRT on cancer cell surfaces acts as an 'eat-me' signal and facilitates improved elimination of stressed and dying tumour cells by DCs. Therefore, therapeutics that promote endogenous CRT translocation to the cell surface can improve the removal of cancer cells. However, infused recombinant CRT dampens this cancer cell eradication by binding directly to the DCs. Low levels of endogenous BiP appear as a surface biomarker of endoplasmic reticulum (ER) stress in some types of tumour cells, a reflection of cells undergoing proliferation, in which resulting hypoxia and nutrient deprivation perturb ER homeostasis triggering the unfolded protein response, leading to increased expression of GRP78/BiP and altered cellular location. Conversely, infusion of an analogue of GRP78/BiP (IRL201805) can lead to long-term immune resetting and restoration of immune homeostasis. The therapeutic potential of both chaperones relies on them being relocated from their intracellular ER environment. Ongoing clinical trials are employing therapeutic interventions to either enhance endogenous cell surface CRT or infuse IRL201805, thereby triggering several disease-relevant immune responses leading to a beneficial clinical outcome.

Keywords:  anti-inflammatory; autoimmunity; cancer; myeloid cells; tolerance

DOI:  https://doi.org/10.1111/jcmm.17669