bims-unfpre 2022-12-18 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–12–18
nine papers selected by
Susan Logue, University of Manitoba

Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model.
Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress.
Endoplasmic Reticulum Stress Signaling and Neuronal Cell Death.
Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy.
ER stress-related mRNA-lncRNA co-expression gene signature predicts the prognosis and immune implications of esophageal cancer.
Co-chaperones of the Human Endoplasmic Reticulum: An Update.
New Visions on Natural Products and Cancer Therapy: Autophagy and Related Regulatory Pathways.
Regulation of RNA localization during oocyte maturation by dynamic RNA-ER association and remodeling of the ER.
CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.

Blood Adv. 2022 Dec 12. pii: bloodadvances.2022008457. [Epub ahead of print]

Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model.

Angelina J Lay, Alexander Dupuy, Lejla Hagimola, Jessica Tieng, Mark Larance, Yunwei Zhang, Jean Yang, Yvonne Xiangyue Kong, Joyce Chiu, Emilia Charlotte Gray, Zihao Qin, Diana Schmidt, Jessica A A Maclean, Benjamin Rink Hofma, Marc L Ellis, Maggie L Kalev-Zylinska, Yair Argon, Shaun P Jackson, Philip Hogg, Freda H Passam.

Extracellular protein disulfide isomerases (PDIs), including PDI, endoplasmic reticulum protein 57 (ERp57), ERp72, ERp46 and ERp5, are required for in vivo thrombus formation in mice. Platelets secrete PDIs upon activation, which regulate platelet aggregation. However, platelets secrete only ~10% of their PDI content extracellularly. The intracellular role of PDIs in platelet function is unknown. In the current study, we aimed to characterize the role of ERp5 (gene Pdia6) using platelet conditional knockout mice, platelet factor 4 (Pf4) Cre+/ERp5fl/fl. Pf4Cre+/ERp5fl/fl mice developed mild macrothrombocytopenia. Platelets deficient in ERp5 showed marked dysregulation of their ER, indicated by a 2-fold upregulation of ER proteins, including PDI, ERp57, ERp72, ERp46, 78 kDa glucose-regulated protein (GRP78) and calreticulin. ERp5 deficient platelets showed an enhanced ER stress response to ex vivo and in vivo ER stress inducers, with enhanced phosphorylation of eukaryotic translation initiation factor 2A (eIF2a) and inositol-requiring enzyme 1 (IRE1). ERp5 deficiency was associated with increased secretion of PDIs, an enhanced response to thromboxane A2 (TXA2) receptor activation, and increased thrombus formation in vivo. Our results support that ERp5 acts as negative regulator of ER stress responses in platelets, and highlights the importance of a disulfide isomerase in platelet ER homeostasis. The results also indicate a previously unanticipated role of platelet ER stress in platelet secretion and thrombosis. This may have important implications for therapeutic applications of ER stress inhibitors in thrombosis.

DOI: https://doi.org/10.1182/bloodadvances.2022008457
Proc Natl Acad Sci U S A. 2022 Dec 20. 119(51): e2214957119

Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress.

Hui-Hsing Hung, Yasuko Nagatsuka, Tatiana Soldà, Vamsi K Kodali, Kazuhisa Iwabuchi, Hiroyuki Kamiguchi, Koki Kano, Ichiro Matsuo, Kazutaka Ikeda, Randal J Kaufman, Maurizio Molinari, Peter Greimel, Yoshio Hirabayashi.

  Secretory proteins and lipids are biosynthesized in the endoplasmic reticulum (ER). The "protein quality control" system (PQC) monitors glycoprotein folding and supports the elimination of terminally misfolded polypeptides. A key component of the PQC system is Uridine diphosphate glucose:glycoprotein glucosyltransferase 1 (UGGT1). UGGT1 re-glucosylates unfolded glycoproteins, to enable the re-entry in the protein-folding cycle and impede the aggregation of misfolded glycoproteins. In contrast, a complementary "lipid quality control" (LQC) system that maintains lipid homeostasis remains elusive. Here, we demonstrate that cytotoxic phosphatidic acid derivatives with saturated fatty acyl chains are one of the physiological substrates of UGGT2, an isoform of UGGT1. UGGT2 produces lipid raft-resident phosphatidylglucoside regulating autophagy. Under the disruption of lipid metabolism and hypoxic conditions, UGGT2 inhibits PERK-ATF4-CHOP-mediated apoptosis in mouse embryonic fibroblasts. Moreover, the susceptibility of UGGT2 KO mice to high-fat diet-induced obesity is elevated. We propose that UGGT2 is an ER-localized LQC component that mitigates saturated lipid-associated ER stress via lipid glucosylation.

Keywords:  CHOP; UGGT; hypoxia; phosphatidylglucoside; saturated lipid

DOI:  https://doi.org/10.1073/pnas.2214957119
Int J Mol Sci. 2022 Dec 02. pii: 15186. [Epub ahead of print]23(23):

Endoplasmic Reticulum Stress Signaling and Neuronal Cell Death.

Adalberto Merighi, Laura Lossi.

  Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca2+ homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.

Keywords:  apoptosis; autophagy; cerebellar granule cells; endoplasmic reticulum; endoplasmic reticulum stress; unfolded protein response

DOI:  https://doi.org/10.3390/ijms232315186
Cells. 2022 Nov 25. pii: 3773. [Epub ahead of print]11(23):

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy.

Rashedul Alam, Mohammad Fazlul Kabir, Hyung-Ryong Kim, Han-Jung Chae.

  Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment.

Keywords:  ER stress; UPR; autophagy; cancer therapy; tumerogenesis

DOI:  https://doi.org/10.3390/cells11233773
Am J Transl Res. 2022 ;14(11): 8064-8084

ER stress-related mRNA-lncRNA co-expression gene signature predicts the prognosis and immune implications of esophageal cancer.

Feng Li, Jiahao Ma, Cheng Yan, Yonghua Qi.

BACKGROUND: Esophageal cancer (EC) is one of the most common malignant cancers in the world. Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and has been implicated in the development of various types of cancer. Long noncoding RNAs (lncRNAs) refer to a group of noncoding RNAs (ncRNAs), which regulate gene expression by interacting with DNA, RNA and proteins. Accumulating evidence suggests that lncRNAs are critical regulators of gene expression in development, differentiation, and human diseases, such as cancers and heart diseases. However, the prognostic model of EC based on ER stress-related mRNA and lncRNA has not been reported.
METHODS: Firstly, we downloaded RNA expression profiles from The Cancer Genome Atlas (TCGA) and obtained ER stress-related genes from the Molecular Signature Database (MSigDB). Next, Weighted Correlation Network Analysis (WGCNA) co-expression analysis was used to identify survival-related ER stress-related modules. Prognostic models were developed using univariate and Least absolute shrinkage and selection operator (LASSO) regression analyses on the training set and validated on the test set. Afterwards, The Receiver Operating Characteristic (ROC) curve and nomogram were used to evaluate the performance of risk prediction models. Differentially expressed gene (DEG) and enrichment analysis were performed between different groups in order to identify the biological processes correlated with the risk score. Finally, the fraction of immune cell infiltration and the difference of tumor microenvironment were identified in high-risk and low-risk groups.
RESULTS: The WGCNA co-expression analysis identified 49 ER genes that are highly associated with EC prognosis. Using univariate Cox regression and LASSO regression analysis, we developed prognostic risk models based on nine signature genes (four mRNAs and five lncRNAs). Both in the training and in the test sets, the overall survival (OS) of EC patients in the high-risk group was significantly lower than that in the low-risk group. The Kaplan-Meier curve and the ROC curve demonstrate the prognostic model we built can precisely predict the survival with more than 70% accuracy. The correlation analysis between the risk score and the infiltration of immune cells showed that the model can indicate the state of the immune microenvironment in EC.
CONCLUSION: In this study, we developed a novel prognostic model for esophageal cancer based on ER stress-related mRNA-lncRNA co-expression profiles that could predict the prognosis, immune cell infiltration, and immunotherapy response in patients with EC. Our results also may provide clinicians with a quantitative tool to predict the survival time of patients and help them individualize treatment strategies for the patients with EC.

Keywords: Esophageal cancer; endoplasmic reticulum stress; lncRNA; mRNA; prognostic model
Subcell Biochem. 2023 ;101 247-291

Co-chaperones of the Human Endoplasmic Reticulum: An Update.

Armin Melnyk, Sven Lang, Mark Sicking, Richard Zimmermann, Martin Jung.

  In mammalian cells, the rough endoplasmic reticulum (ER) plays central roles in the biogenesis of extracellular plus organellar proteins and in various signal transduction pathways. For these reasons, the ER comprises molecular chaperones, which are involved in import, folding, assembly, export, plus degradation of polypeptides, and signal transduction components, such as calcium channels, calcium pumps, and UPR transducers plus adenine nucleotide carriers/exchangers in the ER membrane. The calcium- and ATP-dependent ER lumenal Hsp70, termed immunoglobulin heavy-chain-binding protein or BiP, is the central player in all these activities and involves up to nine different Hsp40-type co-chaperones, i.e., ER membrane integrated as well as ER lumenal J-domain proteins, termed ERj or ERdj proteins, two nucleotide exchange factors or NEFs (Grp170 and Sil1), and NEF-antagonists, such as MANF. Here we summarize the current knowledge on the ER-resident BiP/ERj chaperone network and focus on the interaction of BiP with the polypeptide-conducting and calcium-permeable Sec61 channel of the ER membrane as an example for BiP action and how its functional cycle is linked to ER protein import and various calcium-dependent signal transduction pathways.

Keywords:  ATP/ADP exchange; Calcium-dependent signal transduction; Cellular calcium homeostasis; ER calcium leakage; ER energy homeostasis; ER protein import; ER-associated protein degradation; Human endoplasmic reticulum; J-domain proteins; Protein folding

DOI:  https://doi.org/10.1007/978-3-031-14740-1_9
Cancers (Basel). 2022 Nov 26. pii: 5839. [Epub ahead of print]14(23):

New Visions on Natural Products and Cancer Therapy: Autophagy and Related Regulatory Pathways.

Alma Martelli, Marzieh Omrani, Maryam Zarghooni, Valentina Citi, Simone Brogi, Vincenzo Calderone, Antoni Sureda, Shahrokh Lorzadeh, Simone C da Silva Rosa, Beniamin Oscar Grabarek, Rafał Staszkiewicz, Marek J Los, Seyed Fazel Nabavi, Seyed Mohammad Nabavi, Parvaneh Mehrbod, Daniel J Klionsky, Saeid Ghavami.

  Macroautophagy (autophagy) has been a highly conserved process throughout evolution and allows cells to degrade aggregated/misfolded proteins, dysfunctional or superfluous organelles and damaged macromolecules, in order to recycle them for biosynthetic and/or energetic purposes to preserve cellular homeostasis and health. Changes in autophagy are indeed correlated with several pathological disorders such as neurodegenerative and cardiovascular diseases, infections, cancer and inflammatory diseases. Conversely, autophagy controls both apoptosis and the unfolded protein response (UPR) in the cells. Therefore, any changes in the autophagy pathway will affect both the UPR and apoptosis. Recent evidence has shown that several natural products can modulate (induce or inhibit) the autophagy pathway. Natural products may target different regulatory components of the autophagy pathway, including specific kinases or phosphatases. In this review, we evaluated ~100 natural compounds and plant species and their impact on different types of cancers via the autophagy pathway. We also discuss the impact of these compounds on the UPR and apoptosis via the autophagy pathway. A multitude of preclinical findings have shown the function of botanicals in regulating cell autophagy and its potential impact on cancer therapy; however, the number of related clinical trials to date remains low. In this regard, further pre-clinical and clinical studies are warranted to better clarify the utility of natural compounds and their modulatory effects on autophagy, as fine-tuning of autophagy could be translated into therapeutic applications for several cancers.

Keywords:  apoptosis; autophagy; autophagy-related diseases; cancer; natural compound; unfolded protein response

DOI:  https://doi.org/10.3390/cancers14235839
Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01690-4. [Epub ahead of print]41(11): 111802

Regulation of RNA localization during oocyte maturation by dynamic RNA-ER association and remodeling of the ER.

Hyojeong Hwang, Seongmin Yun, Rachel Braz Arcanjo, Divyanshi, Sijie Chen, Wenyan Mei, Romana A Nowak, Taejoon Kwon, Jing Yang.

  Asymmetric localization of mRNAs is crucial for cell polarity and cell fate determination. By performing fractionation RNA-seq, we report here that a large number of maternal RNAs are associated with the ER in Xenopus oocytes but are released into the cytosol after oocyte maturation. We provide evidence that the majority of ER-associated RNA-binding proteins (RBPs) remain associated with the ER after oocyte maturation. However, all ER-associated RBPs analyzed exhibit reduced binding to some of their target RNAs after oocyte maturation. Our results further show that the ER is remodeled massively during oocyte maturation, leading to the formation of a widespread tubular ER network in the animal hemisphere that is required for the asymmetric localization of mRNAs in mature eggs. Thus, our findings demonstrate that dynamic regulation of RNA-ER association and remodeling of the ER are important for the asymmetric localization of RNAs during development.

Keywords:  CP: Cell biology; CP: Developmental biology; RNA localization; Xenopus; endoplasmic reticulum; maternal RNAs; oocyte maturation

DOI:  https://doi.org/10.1016/j.celrep.2022.111802
Cell Tissue Res. 2022 Dec 16.

CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.

Lin Chen, Ling Pan, Yuexi Zeng, Xiaonan Zhu, Li You.

  Sarcopenia is characterized by a progressive reduction in muscle mass or muscle physiological function associated with aging, but the relevant molecular mechanisms are not clear. Here, we identify the role of the myogenesis modifier CPNE1 in sarcopenia. CPNE1 is upregulated in aged skeletal muscles and young skeletal muscle satellite cells with palmitate-induced atrophy. The overexpression of CPNE1 hinders proliferation and differentiation and increases muscle atrophy characteristics in young skeletal muscle-derived satellite cells. In addition, CPNE1 overexpression disrupts the balance of mitochondrial fusion and division and causes endoplasmic reticulum stress. We found that the effects of CPNE1 on mitochondrial function are dependent on the PERK/eIF2α/ATF4 pathway. The overexpression of CPNE1 in young muscles alters membrane lipid composition, reduces skeletal muscle fibrosis regeneration, and exercise capacity in mice. These effects were reversed by PERK inhibitor GSK2606414. Moreover, immunoprecipitation indicates that CPNE1 overexpression greatly increased the acetylation of PERK. Therefore, CPNE1 is an important modifier that drives mitochondrial homeostasis to regulate myogenic cell proliferation and differentiation via the PERK-eIF2α pathway, which could be a valuable target for age-related sarcopenia.

Keywords:  CPNE1; Endoplasmic reticulum stress; PERK; Sarcopenia; eIF2α

DOI:  https://doi.org/10.1007/s00441-022-03720-y