bims-unfpre 2024-06-09 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024‒06‒09
ten papers selected by
Susan Logue, University of Manitoba

IRE1α Mediates the Hypertrophic Growth of Cardiomyocytes Through Facilitating the Formation of Initiation Complex to Promote the Translation of TOP-Motif Transcripts.
Redox regulation of UPR signalling and mitochondrial ER contact sites.
The lipid side of unfolded protein response.
Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death.
p20BAP31 promotes cell apoptosis via interaction with GRP78 and activating the PERK pathway in colorectal cancer.
Tumour suppressor protein sMEK1 links to IRE1 signalling pathway to modulate its activity during ER stress.
ER stress inhibition enhances formation of triacylglcerols and protects endothelial cells from lipotoxicity.
Triple threat: neutrophil ER stress, NETosis, airway inflammation escalation.
FADS2 confers SCD1 inhibition resistance to cancer cells by modulating the ER stress response.
Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity.

Circulation. 2024 Jun 05.

IRE1α Mediates the Hypertrophic Growth of Cardiomyocytes Through Facilitating the Formation of Initiation Complex to Promote the Translation of TOP-Motif Transcripts.

Chao Li, Shiqian Li, Guangyu Zhang, Qinfeng Li, Weidan Song, Xiaoding Wang, Jane A Cook, Miesje van der Stoel, Bradley W Wright, Francisco Altamirano, Erica L Niewold, Jungsoo Han, Garrett Kimble, Pengfei Zhang, Xiang Luo, Hery Urra, Herman I May, Anwarul Ferdous, Xue-Nan Sun, Yingfeng Deng, Elina Ikonen, Claudio Hetz, Randal J Kaufman, Kezhong Zhang, Thomas G Gillette, Philipp E Scherer, Joseph A Hill, Jin Chen, Zhao V Wang.

  BACKGROUND: Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms.METHODS: Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control.
RESULTS: We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5' terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5' untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo.
CONCLUSIONS: These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.

Keywords:  EGFR protein, mouse; heart failure; hypertrophy; protein synthesis inhibitors

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067606
Cell Mol Life Sci. 2024 Jun 07. 81(1): 250

Redox regulation of UPR signalling and mitochondrial ER contact sites.

Jose C Casas-Martinez, Afshin Samali, Brian McDonagh.

  Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.

Keywords:   C. elegans ; Contact-sites; Hormesis; Mitochondrial dynamics; Redox signalling; Skeletal muscle

DOI:  https://doi.org/10.1007/s00018-024-05286-0
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jun 04. pii: S1388-1981(24)00065-9. [Epub ahead of print] 159515

The lipid side of unfolded protein response.

Wojciech Białek, Anita Hryniewicz-Jankowska, Paulina Czechowicz, Jakub Sławski, James F Collawn, Aleksander Czogalla, Rafał Bartoszewski.

  Although our current knowledge of the molecular crosstalk between the ER stress, the unfolded protein response (UPR), and lipid homeostasis remains limited, there is increasing evidence that dysregulation of either protein or lipid homeostasis profoundly affects the other. Most research regarding UPR signaling in human diseases has focused on the causes and consequences of disrupted protein folding. The UPR itself consists of very complex pathways that function to not only maintain protein homeostasis, but just as importantly, modulate lipid biogenesis to allow the ER to adjust and promote cell survival. Lipid dysregulation is known to activate many aspects of the UPR, but the complexity of this crosstalk remains a major research barrier. ER lipid disequilibrium and lipotoxicity are known to be important contributors to numerous human pathologies, including insulin resistance, liver disease, cardiovascular diseases, neurodegenerative diseases, and cancer. Despite their medical significance and continuous research, however, the molecular mechanisms that modulate lipid synthesis during ER stress conditions, and their impact on cell fate decisions, remain poorly understood. Here we summarize the current view on crosstalk and connections between altered lipid metabolism, ER stress, and the UPR.

Keywords:  ER stress; Lipid membrane homeostasis; Lipid metabolism

DOI:  https://doi.org/10.1016/j.bbalip.2024.159515
Front Pharmacol. 2024 ;15 1397116

Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death.

Wang Liu, Chenchen He, Changlin Li, Shazhou Ye, Jiang Zhao, Cunle Zhu, Xiangwei Wang, Qi Ma, Benyi Li.

  Background: Alternol is a small molecular compound isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Our previous studies showed that Alternol treatment induced reactive oxygen species (ROS)-dependent immunogenic cell death. This study conducted a comprehensive investigation to explore the mechanisms involved in Alternol-induced immunogenic cell death. Methods: Prostate cancer PC-3, C4-2, and 22RV1 were used in this study. Alternol interaction with heat shock proteins (HSP) was determined using CETSA assay. Alternol-regulated ER stress proteins were assessed with Western blot assay. Extracellular adenosine triphosphate (ATP) was measured using ATPlite Luminescence Assay System. Results: Our results showed that Alternol interacted with multiple cellular chaperone proteins and increased their expression levels, including endoplasmic reticulum (ER) chaperone hypoxia up-regulated 1 (HYOU1) and heat shock protein 90 alpha family class B member 1 (HSP90AB1), as well as cytosolic chaperone heat shock protein family A member 8 (HSPA8). These data represented a potential cause of unfolded protein response (UPR) after Alternol treatment. Further investigation revealed that Alternol treatment triggered ROS-dependent (ER) stress responses via R-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α). The double-stranded RNA-dependent protein kinase (PKR) but not activating transcription factor 6 (ATF6) cascades, leading to ATF-3/ATF-4 activation, C/EBP-homologous protein (CHOP) overexpression, and X-box binding protein XBP1 splicing induction. In addition, inhibition of these ER stress responses cascades blunted Alternol-induced extracellular adenosine triphosphate (ATP) release, one of the classical hallmarks of immunogenic cell death. Conclusion: Taken together, our data demonstrate that Alternol treatment triggered multiple ER stress cascades, leading to immunogenic cell death.

Keywords:  ATP release; Er stress; IRE1α; PERK; heat-shock proteins; prostate cancer

DOI:  https://doi.org/10.3389/fphar.2024.1397116
Int J Biol Macromol. 2024 Jun 04. pii: S0141-8130(24)03675-4. [Epub ahead of print] 132870

p20BAP31 promotes cell apoptosis via interaction with GRP78 and activating the PERK pathway in colorectal cancer.

Xiaohan Jiang, Benzhi Zhu, Guoxun Li, Shuyu Cui, Jiaying Yang, Rui Jiang, Bing Wang.

  Colorectal cancer (CRC) is the second most deadly cancer worldwide. Although various treatments for CRC have made progress, they have limitations. Therefore, the search for new effective molecular targets is important for the treatment of CRC. p20BAP31 induces apoptosis through diverse pathways and exhibits greater sensitivity in CRC. Therefore, a comprehensive exploration of the molecular functions of p20BAP31 is important for its application in anti-tumor therapy. In this study, we showed that exogenous p20BAP31 was still located in the ER and significantly activated the unfolded protein response (UPR) through the PERK pathway. The activation of the PERK pathway is prominent in p20BAP31-induced reactive oxygen species (ROS) accumulation and apoptosis. We found, for the first time, that p20BAP31 leads to ER stress and markedly attenuates tumor cell growth in vivo. Importantly, mechanistic investigations indicated that p20BAP31 competitively binds to GRP78 from PERK and causes hyperactivation of the UPR. Furthermore, p20BAP31 upregulates the expression of GRP78 by promoting HSF1 nuclear translocation and enhancing its binding to the GRP78 promoter. These findings reveal p20BAP31 as a regulator of ER stress and a potential target for tumor therapy, and elucidate the underlying mechanism by which p20BAP31 mediates signal transduction between ER and mitochondria.

Keywords:  Antitumor; GRP78; PERK; Unfolded protein response; p20BAP31

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.132870
Biochim Biophys Acta Mol Cell Res. 2024 Jun 03. pii: S0167-4889(24)00117-4. [Epub ahead of print] 119774

Tumour suppressor protein sMEK1 links to IRE1 signalling pathway to modulate its activity during ER stress.

Ozaira Qadri, Samirul Bashir, Mariam Banday, Nazia Syed, Younis Majeed Bhat, Nida I Fatima, Debnath Pal, Khalid Majid Fazili.

  The Endoplasmic Reticulum is a pervasive, dynamic cellular organelle that performs a wide range of functions in the eukaryotic cell, including protein folding and maturation. Upon stress, ER activates an adaptive cellular pathway, namely Unfolded Protein Response, that transduces information from ER to nucleus, restoring homeostasis in the ER milieu. UPR consists of three membrane-tethered sensors; IRE1, PERK and ATF6. Among all the UPR sensors, the IRE1 branch acts as a central pathway that orchestrates several pathways to determine cell fate. However, the detailed knowledge underlying the whole process is not understood yet. Previously, we determined the sMEK1 as one of the interacting partners of IRE1. sMEK1 is a protein phosphatase, which has been indicated in a number of critical cellular functions like apoptosis, cell proliferation, and tumour suppression. In this study, we evaluated the role of sMEK1 on the IRE1 signalling pathway. Our data indicate that sMEK1 can inhibit IRE1 phosphorylation under ER stress. This inhibitory effect of sMEK1 could be reflected in its downstream effectors, Xbp1 and RIDD, which are downregulated in the presence of sMEK1. We also found that the repressing effect of sMEK1 was specific to the IRE1 signalling pathway and could be preserved even under prolonged ER stress. Our findings also indicate that sMEK1 can inhibit IRE1 and its downstream molecules under ER stress irrespective of other UPR sensors. These results help to draw the mechanistic details giving insights into different molecular connections of UPR with other pathways.

Keywords:  Endoplasmic reticulum stress; IRE1; Unfolded protein response; sMEK1

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119774
Cell Commun Signal. 2024 Jun 03. 22(1): 304

ER stress inhibition enhances formation of triacylglcerols and protects endothelial cells from lipotoxicity.

Igor Kovacevic, Paula Henriette Schmidt, Annkatrin Kowalski, Bernd J Helms, Chris H A van de Lest, Alexander Kluttig, Guido Posern.

  Elevated concentrations of palmitate in serum of obese individuals can impair endothelial function, contributing to development of cardiovascular disease. Although several molecular mechanisms of palmitate-induced endothelial dysfunction have been proposed, there is no consensus on what signaling event is the initial trigger of detrimental palmitate effects. Here we report that inhibitors of ER stress or ceramid synthesis can rescue palmitate-induced autophagy impairment in macro- and microvascular endothelial cells. Furthermore, palmitate-induced cholesterol synthesis was reverted using these inhibitors. Similar to cell culture data, autophagy markers were increased in serum of obese individuals. Subsequent lipidomic analysis revealed that palmitate changed the composition of membrane phospholipids in endothelial cells and that these effects were not reverted upon application of above-mentioned inhibitors. However, ER stress inhibition in palmitate-treated cells enhanced the synthesis of trilglycerides and restored ceramide levels to control condition. Our results suggest that palmitate induces ER-stress presumably by shift in membrane architecture, leading to impaired synthesis of triglycerides and enhanced production of ceramides and cholesterol, which altogether enhances lipotoxicity of palmitate in endothelial cells.

Keywords:  Ceramides; ER stress; Endothelial dysfunction; Lipidomic analysis; Obesity

DOI:  https://doi.org/10.1186/s12964-024-01682-y
Trends Cell Biol. 2024 Jun 03. pii: S0962-8924(24)00074-6. [Epub ahead of print]

Triple threat: neutrophil ER stress, NETosis, airway inflammation escalation.

Mohammad Mamun Ur Rashid, Ahsan Ullah, Mst Sahida Khatun, Hyung-Ryong Kim, Han-Jung Chae.

  This report aims to propose the novel term 'neutrophil endoplasmic reticulum (ER) stress' (NERS). NERS explores the influence of neutrophil extracellular trap (NET) formation and exacerbation of respiratory ailments. This inquiry aims to advance comprehension in neutrophil biology and respiratory health.

Keywords:  ER stress; ILIA; NERS; NETosis; infinity loop of inflammation amplification; inflammation; neutrophil

DOI:  https://doi.org/10.1016/j.tcb.2024.04.004
Sci Rep. 2024 Jun 07. 14(1): 13116

FADS2 confers SCD1 inhibition resistance to cancer cells by modulating the ER stress response.

Toshikatsu Ikeda, Yuki Katoh, Hirotsugu Hino, Daichi Seta, Tadashi Ogawa, Takashi Iwata, Hiroshi Nishio, Masaki Sugawara, Shuichi Hirai.

  Stearoyl-CoA desaturase 1 (SCD1) is an attractive target for cancer therapy. However, the clinical efficacy of SCD1 inhibitor monotherapy is limited. There is thus a need to elucidate the mechanisms of resistance to SCD1 inhibition and develop new therapeutic strategies for combination therapy. In this study, we investigated the molecular mechanisms by which cancer cells acquire resistance to endoplasmic reticulum (ER) stress-dependent cancer cell death induced by SCD1 inhibition. SCD1 inhibitor-sensitive and -resistant cancer cells were treated with SCD1 inhibitors in vitro, and SCD1 inhibitor-sensitive cancer cells accumulated palmitic acid and underwent ER stress response-induced cell death. Conversely, SCD1-resistant cancer cells did not undergo ER stress response-induced cell death because fatty acid desaturase 2 (FADS2) eliminated the accumulation of palmitic acid. Furthermore, genetic depletion using siRNA showed that FADS2 is a key determinant of sensitivity/resistance of cancer cells to SCD1 inhibitor. A549 cells, an SCD1 inhibitor-resistant cancer cell line, underwent ER stress-dependent cancer cell death upon dual inhibition of SCD1 and FADS2. Thus, combination therapy with SCD1 inhibition and FADS2 inhibition is potentially a new cancer therapeutic strategy targeting fatty acid metabolism.

Keywords:  Endoplasmic reticulum (ER) stress; Fatty acid desaturase 2 (FADS2); Palmitic acid; Stearoyl-CoA desaturase 1 (SCD1)

DOI:  https://doi.org/10.1038/s41598-024-64043-2
iScience. 2024 Jun 21. 27(6): 109962

Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity.

Mengjia Li, Haocheng Shou, Guillermo Martínez Corrales, Tatiana Svermova, Alessandra Vieira Franco, Nazif Alic.

  Transcription factors can reprogram gene expression to promote longevity. Here, we investigate the role of Drosophila Xbp1. Xbp1 is activated by splicing of its primary transcript, Xbp1u, to generate Xbp1s, a key activator of the endoplasmic reticulum unfolded protein response (UPRER). We show that Xbp1s induces the conical UPRER in the gut, promoting longevity from the resident stem cells. In contrast, in the fat body, Xbp1s does not appear to trigger UPRER but alters metabolic gene expression and is still able to extend lifespan. In the fat body, Xbp1s and dFOXO impinge on the same target genes, including the PGC-1α orthologue Srl, and dfoxo requires Xbp1 to extend lifespan. Interestingly, unspliceable version of the Xbp1 mRNA, Xbp1u can also extend lifespan, hinting at roles in longevity for the poorly characterized Xbp1u transcription factor. These findings reveal the diverse functions of Xbp1 in longevity in the fruit fly.

Keywords:  Biological sciences; Molecular biology; Molecular mechanism of gene regulation

DOI:  https://doi.org/10.1016/j.isci.2024.109962