bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023–01–15
fiveteen papers selected by
Susan Logue, University of Manitoba
  1. Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.
  2. Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR).
  3. New Frontiers on ER Stress Modulation: Are TRP Channels the Leading Actors?
  4. A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity.
  5. Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer.
  6. Folic acid depletion along with inhibition of the PERK arm of endoplasmic reticulum stress pathway promotes a less aggressive phenotype of hepatocellular carcinoma cells.
  7. The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome.
  8. ER stress-associated transcription factor CREB3 is essential for normal Ca2+, ATP, and ROS homeostasis.
  9. Geraniol-Mediated Suppression of Endoplasmic Reticulum Stress Protects against Cerebral Ischemia-Reperfusion Injury via the PERK-ATF4-CHOP Pathway.
  10. Loss of TMCC2 activates endoplasm reticulum stress and causes auditory hair cell death.
  11. PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.
  12. Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.
  13. The Xbp1-regulated transcription factor Mist1 restricts antibody secretion by restraining Blimp1 expression in plasma cells.
  14. Sensitive imaging of Endoplasmic reticulum (ER) autophagy with an acidity-reporting ER-Tracker.
  15. ERASing endoplasmic reticulum stress: the faster, the better.
  1. Nat Commun. 2023 Jan 09. 14(1): 120
    Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.
    Michael J P Crowley, Bhavneet Bhinder, Geoffrey J Markowitz, Mitchell Martin, Akanksha Verma, Tito A Sandoval, Chang-Suk Chae, Shira Yomtoubian, Yang Hu, Sahil Chopra, Diamile A Tavarez, Paolo Giovanelli, Dingcheng Gao, Timothy E McGraw, Nasser K Altorki, Olivier Elemento, Juan R Cubillos-Ruiz, Vivek Mittal.
      IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.
    DOI:  https://doi.org/10.1038/s41467-022-35584-9
  2. Int J Mol Sci. 2022 Dec 29. pii: 577. [Epub ahead of print]24(1):
    Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR).
    Gehan Botrus, Richard M Miller, Pedro Luiz Serrano Uson Junior, Geoffrey Kannan, Haiyong Han, Daniel D Von Hoff.
      High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1α, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death.
    Keywords:  apoptosis; endoplasmic reticulum (ER) stress; pancreatic cancer; unfolded protein response (UPR)
    DOI:  https://doi.org/10.3390/ijms24010577
  3. Int J Mol Sci. 2022 Dec 22. pii: 185. [Epub ahead of print]24(1):
    New Frontiers on ER Stress Modulation: Are TRP Channels the Leading Actors?
    Vincenzo Vestuto, Veronica Di Sarno, Simona Musella, Giorgio Di Dona, Ornella Moltedo, Isabel Maria Gomez-Monterrey, Alessia Bertamino, Carmine Ostacolo, Pietro Campiglia, Tania Ciaglia.
      The endoplasmic reticulum (ER) is a dynamic structure, playing multiple roles including calcium storage, protein synthesis and lipid metabolism. During cellular stress, variations in ER homeostasis and its functioning occur. This condition is referred as ER stress and generates a cascade of signaling events termed unfolded protein response (UPR), activated as adaptative response to mitigate the ER stress condition. In this regard, calcium levels play a pivotal role in ER homeostasis and therefore in cell fate regulation since calcium signaling is implicated in a plethora of physiological processes, but also in disease conditions such as neurodegeneration, cancer and metabolic disorders. A large body of emerging evidence highlighted the functional role of TRP channels and their ability to promote cell survival or death depending on endoplasmic reticulum stress resolution, making them an attractive target. Thus, in this review we focused on the TRP channels' correlation to UPR-mediated ER stress in disease pathogenesis, providing an overview of their implication in the activation of this cellular response.
    Keywords:  ER stress; TRP channels; UPR; cancer; inflammation; metabolic diseases; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms24010185
  4. Cancers (Basel). 2022 Dec 31. pii: 293. [Epub ahead of print]15(1):
    A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity.
    Daniela Correia da Silva, Patrícia Valentão, David M Pereira.
      The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road toward desirable success rates of cancer treatments is still long and paved with uncertainty. This work aims to select natural products that act via endoplasmic reticulum (ER) stress, a known vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Among an in-house chemical library, nontoxic molecules towards noncancer cells were assessed for toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. Active molecules towards at least one of these cell lines were studied in a battery of ensuing assays to clarify the involvement of ER stress and unfolded protein response (UPR) in the cytotoxic effect. Several natural products are selectively cytotoxic against malignant cells, and the effect often relies on ER stress induction. Berberine was the most promising molecule, being active against both cell models by disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation. Our results indicate that berberine and emodin are potential leads for the development of more potent ER stressors to be used as selective anticancer agents.
    Keywords:  ATF4; CHOP; EDEM1; calcium homeostasis; caspase-4; chemical library; drug discovery; endoplasmic reticulum stress; natural products; unfolded protein response
    DOI:  https://doi.org/10.3390/cancers15010293
  5. Sci Rep. 2023 Jan 13. 13(1): 693
    Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer.
    Ankang Hu, Jing Liu, Yonghui Wang, Maoyin Zhang, Yao Guo, Ying Qin, Tingya Liu, Yanjuan Men, Quangang Chen, Tingjun Liu.
      Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases, is associated with a poor outcome. Rafoxanide is an anthelmintic drug that inhibits tumor growth in certain malignancies. However, its impact on NSCLC remains unknown. In this study, we examined the effect of rafoxanide on NSCLC and dissected the underlying mechanism. The results showed that rafoxanide significantly inhibited the growth, invasion, and migration of NSCLC cells. Besides, rafoxanide can induce NSCLC cell apoptosis and cell cycle arrest in a dose-dependent manner. RNA-seq analysis revealed that genes associated with endoplasmic reticulum stress (ER) stress responses were activated. Mechanistically, we found Rafoxanide can induce ER stress and activate the unfolded protein response (UPR). Apoptosis was activated by excessive ER stress, and autophagy was activated to partially alleviate ER stress. In vivo, we found that rafoxanide inhibited the growth of A549 and H1299 xenograft mouse models without severe side effects. Collectively, the present study indicates that rafoxanide may be a candidate drug for the treatment of NSCLC.
    DOI:  https://doi.org/10.1038/s41598-023-27403-y
  6. Mol Cell Biochem. 2023 Jan 07.
    Folic acid depletion along with inhibition of the PERK arm of endoplasmic reticulum stress pathway promotes a less aggressive phenotype of hepatocellular carcinoma cells.
    Himanshi Goyal, Renuka Sharma, Dikshit Lamba, Jyotdeep Kaur.
      Folate is a vital vitamin involved in one-carbon metabolism and any changes in folate status may lead to epigenetic alterations. It is already known that stages and liver cancer progression are negatively correlated with folate levels. Nevertheless, mechanisms involved in folate deficiency in HCC (Hepatocellular carcinoma) are still not completely understood. So, this study tests the hypothesis that due to the increased demand for ER (endoplasmic reticulum) proteins, folate deficiency might lead to the induction of UPR (unfolded protein response), which is further correlated with HCC outcomes. HCC cells were cultured in both folate normal (FN) and folate deficient (FD) conditions and the expression of genes of ER stress pathway was investigated. The results demonstrated activation of UPR via induction of PERK, ATF4, and LAMP3. Besides this, FD reduced the migratory capacity and the invasiveness of HCC cells along with the reduction in mesenchymal markers like vimentin but increased apoptosis. Treatment with GSK2606414 (PERK inhibitor) decreased the FD induced expression of PERK, ATF4, and LAMP3 in FD cells. Also, GSK2606414 was found to increase apoptotic cell death and to further reduce the cancer hallmarks selectively in FD cells but not in FN cells. Altogether, our data suggest that targeting the ER stress pathway along with folate deficiency may provide a more promising elimination of the metastatic potential of HCC cells contributing to more effective therapeutic agents.
    Keywords:  Apoptosis; Folate deficiency (FD); Folic acid; HepG2 cells; Hepatocellular carcinoma; Invasion; Migration
    DOI:  https://doi.org/10.1007/s11010-022-04651-6
  7. Int J Mol Sci. 2022 Dec 23. pii: 230. [Epub ahead of print]24(1):
    The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome.
    Shuntaro Morikawa, Fumihiko Urano.
      The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of "poorly folded proteins", namely, the induction of pathogenic ER stress in pancreatic β-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic β-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction.
    Keywords:  ER stress; WFS1; Wolfram syndrome; endoplasmic reticulum; type 2 diabetes; β-cell dysfunction
    DOI:  https://doi.org/10.3390/ijms24010230
  8. Mitochondrion. 2023 Jan 07. pii: S1567-7249(23)00001-6. [Epub ahead of print]
    ER stress-associated transcription factor CREB3 is essential for normal Ca2+, ATP, and ROS homeostasis.
    Brandon S Smith, Tristen Hewitt, Marica Bakovic, Ray Lu.
      In mammalian cells, mitochondrial respiration produces reactive oxygen species (ROS) such as superoxide (O2-), which is then converted by the SOD1 enzyme into hydrogen peroxide (H2O2), the predominant form of cytosolic ROS. ROS at high levels can be toxic, but below this threshold are important for physiological processes acting as a second messenger similar to Ca2+. Mitochondrial Ca2+ influx from the ER increases ATP and ROS production, while ATP and ROS can regulate Ca2+ homeostasis, leading to an intricate interplay between Ca2+, ROS, and ATP synthesis. The Unfolded Protein Response (UPR) proteins ATF6α and XBP1 contribute to protection from oxidative stress through upregulation of Sod1 and Catalase genes. Here, UPR-associated protein CREB3 is shown to play a role in balancing Ca2+, ROS, and ATP homeostasis. Creb3-deficient mouse embryonic fibroblast cells (MEF-/-) were susceptible to H2O2-induced oxidative stress while having a functioning antioxidant gene expression response compared to MEF+/+. MEF-/- cells also contained elevated basal cytosolic ROS levels, which was attributed to drastically increased basal mitochondrial respiration and spare respiratory capacity relative to MEF+/+. MEF-/- cells also showed an increase in endoplasmic reticulum Ca2+ release and mitochondrial Ca2+ levels hinting at a potential cause for MEF-/- cell mitochondrial dysfunction. These results suggest that CREB3 is essential for maintaining proper Ca2+, ATP, and ROS homeostasis in mammalian cells.
    Keywords:  CREB3; Calcium; Cellular Respiration; Homeostasis; Mitochondria; Oxidative Stress; Reactive Oxygen Species
    DOI:  https://doi.org/10.1016/j.mito.2023.01.001
  9. Int J Mol Sci. 2022 Dec 29. pii: 544. [Epub ahead of print]24(1):
    Geraniol-Mediated Suppression of Endoplasmic Reticulum Stress Protects against Cerebral Ischemia-Reperfusion Injury via the PERK-ATF4-CHOP Pathway.
    Yu Wu, Xiaomei Fan, Sha Chen, Ling Deng, Lu Jiang, Shaonan Yang, Zhi Dong.
      Endoplasmic reticulum (ER) stress plays an important role in cerebral ischemia-reperfusion injury (CIRI). Geraniol has antioxidant, antibacterial, and anti-inflammatory activities. Studies have shown that geraniol has a protective effect against CIRI in rats, but the exact mechanism is unclear. Purpose: The aim of this study was to investigate the protective mechanism of geraniol against CIRI. We established a middle cerebral artery occlusion reperfusion model in rats and a PC12 cell oxygen-glucose deprivation/reoxygenation (OGD/R) model to observe the neuroprotective effects of geraniol. Neurological scoring, 2,3,5-triphenyltetrazolium chloride staining, and hematoxylin and eosin staining were used to evaluate the neuroprotective effects of geraniol against CIRI. ER-stress-related and apoptosis-related protein expression was detected via Western blotting and immunofluorescence. Apoptosis was also detected via TUNEL assays and flow cytometry. The fluorescent detection of intracellular calcium was achieved using fluorescent calcium-binding dyes, and transmission electron microscopy was used to assess the neuronal ultrastructure. Geraniol effectively attenuated cerebral infarction and pathological injury after CIRI, had a protective effect against CIRI, significantly reduced the expression of the ER-stress-related proteins P-PERK, ATF4, CHOP, and GRP78 and the pro-apoptotic protein BAX, increased the expression of the anti-apoptotic protein BCL-2, and reduced the occurrence of apoptosis. In the OGD/R model in PC12 cells, the protective effect of geraniol was the same as that in vivo. Our results suggest that geraniol has a protective effect against ischemic stroke by a mechanism possibly related to ER stress via the PERK-ATF4-CHOP pathway.
    Keywords:  apoptosis; cerebral ischemia–reperfusion injury (CIRI); endoplasmic reticulum (ER) stress; geraniol
    DOI:  https://doi.org/10.3390/ijms24010544
  10. Hum Mol Genet. 2023 Jan 06. pii: ddad003. [Epub ahead of print]
    Loss of TMCC2 activates endoplasm reticulum stress and causes auditory hair cell death.
    Rui Ren, Haiyue Xing, Xiaoying Wang, Haibo Du, Yanfei Wang, Zhigang Xu.
      As the auditory and balance receptor cells in the inner ear, hair cells are responsible for converting mechanical stimuli into electrical signals, a process referred to as mechano-electrical transduction (MET). Hair cell development and function are tightly regulated, and hair cell deficits are the main reasons for hearing loss and balance disorders. TMCC2 is an endoplasmic reticulum (ER)-residing transmembrane protein whose physiological function largely remains unknown. In the present work, we show that Tmcc2 is specifically expressed in the auditory hair cells of mouse inner ear. Tmcc2 knockout mice were then established to investigate its physiological role in hearing. Auditory brainstem responses (ABR) measurements show that Tmcc2 knockout mice suffer from congenital hearing loss. Further investigations reveal progressive auditory hair cell loss in Tmcc2 knockout mice. The general morphology and function of ER is unaffected in Tmcc2 knockout hair cells. However, increased ER stress was observed in Tmcc2 knockout mice and knockdown cells, suggesting that loss of TMCC2 leads to auditory hair cell death through elevated ER stress.
    DOI:  https://doi.org/10.1093/hmg/ddad003
  11. Front Endocrinol (Lausanne). 2022 ;13 1053882
    PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.
    Chien-Hsing Lee, Chi-Fu Chiang, Fu-Huang Lin, Feng-Chih Kuo, Sheng-Chiang Su, Chia-Luen Huang, Peng-Fei Li, Jhih-Syuan Liu, Chieh-Hua Lu, Chang-Hsun Hsieh, Yi-Jen Hung, Yi-Shing Shieh.
       Introduction: Endoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle.
    Methods: Herein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4.
    Results: In C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects.
    Discussion: Thus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.
    Keywords:  Endoplasmic reticulum; PDIA4; insulin resistance; metformin; skeletal muscle
    DOI:  https://doi.org/10.3389/fendo.2022.1053882
  12. Cell Chem Biol. 2022 Dec 31. pii: S2451-9456(22)00454-8. [Epub ahead of print]
    Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.
    Shuhong Sun, Chao Wang, Pei Zhao, Gabe M Kline, Julia M D Grandjean, Xin Jiang, Richard Labaudiniere, R Luke Wiseman, Jeffery W Kelly, William E Balch.
      Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and function at a residue-by-residue level by pharmacological activation of the ATF6 arm of the unfolded protein response (UPR). We show that ATF6 activators increase AAT neutrophil elastase (NE) inhibitory activity, while reducing polymer accumulation for the majority of AATD variants, including the prominent Z variant. GP-based profiling of the residue-by-residue response to ATF6 activators captures an unexpected role of the "gate" area in managing AAT-specific activity. Our work establishes a new spatial covariant (SCV) understanding of the convertible state of the protein fold in response to genetic perturbation and active environmental management by proteostasis enhancement for precision medicine.
    Keywords:  Gaussian process; activating transcription factor 6 (ATF6); alpha-1 antitrypsin; alpha-1 antitrypsin deficiency; chaperones; genetic variation; machine learning; pharmacological ATF6 activators; precision medicine; protein aggregation; protein folding; protein misfolding disease; proteostasis; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.chembiol.2022.12.004
  13. Front Immunol. 2022 ;13 859598
    The Xbp1-regulated transcription factor Mist1 restricts antibody secretion by restraining Blimp1 expression in plasma cells.
    Miriam Wöhner, Theresa Pinter, Peter Bönelt, Astrid Hagelkruys, Daniela Kostanova-Poliakova, Johannes Stadlmann, Stephen F Konieczny, Maria Fischer, Markus Jaritz, Meinrad Busslinger.
      Antibody secretion by plasma cells provides acute and long-term protection against pathogens. The high secretion potential of plasma cells depends on the unfolded protein response, which is controlled by the transcription factor Xbp1. Here, we analyzed the Xbp1-dependent gene expression program of plasma cells and identified Bhlha15 (Mist1) as the most strongly activated Xbp1 target gene. As Mist1 plays an important role in other secretory cell types, we analyzed in detail the phenotype of Mist1-deficient plasma cells in Cd23-Cre Bhlha15 fl/fl mice under steady-state condition or upon NP-KLH immunization. Under both conditions, Mist1-deficient plasma cells were 1.4-fold reduced in number and exhibited increased IgM production and antibody secretion compared to control plasma cells. At the molecular level, Mist1 regulated a largely different set of target genes compared with Xbp1. Notably, expression of the Blimp1 protein, which is known to activate immunoglobulin gene expression and to contribute to antibody secretion, was 1.3-fold upregulated in Mist1-deficient plasma cells, which led to a moderate downregulation of most Blimp1-repressed target genes in the absence of Mist1. Importantly, a 2-fold reduction of Blimp1 (Prdm1) expression was sufficient to restore the cell number and antibody expression of plasma cells in Prdm1 Gfp/+ Cd23-Cre Bhlha15 fl/fl mice to the same level seen in control mice. Together, these data indicate that Mist1 restricts antibody secretion by restraining Blimp1 expression, which likely contributes to the viability of plasma cells.
    Keywords:  Blimp1 (Prdm1); Mist1 (Bhlha15); XBP1; antibody secretion; gene regulation; plasma cell differentiation; unfolded protein response (UPR)
    DOI:  https://doi.org/10.3389/fimmu.2022.859598
  14. Autophagy. 2023 Jan 12. 1-11
    Sensitive imaging of Endoplasmic reticulum (ER) autophagy with an acidity-reporting ER-Tracker.
    Yilong Shi, Xiaoxue Zou, Xianghui Zheng, Yimin Wu, Jiahuai Han, Shoufa Han.
      Macroautophagic/autophagic turnover of endoplasmic reticulum (reticulophagy) is critical for cell health. Herein we reported a sensitive fluorescence-on imaging of reticulophagy using a small molecule probe (ER-proRed) comprised of green-emissive fluorinated rhodol for ER targeting and nonfluorescent rhodamine-lactam prone to lysosome-triggered red fluorescence. Partitioned in ER to exhibit green fluorescence, ER-proRed gives intense red fluorescence upon co-delivery with ER into acidic lysosomes. Serving as the signal of reticulophagy, the turning on of red fluorescence enables discernment of reticulophagy induced by starvation, varied levels of reticulophagic receptors, and chemical agents such as etoposide and sodium butyrate. These results show ER probes optically activatable in lysosomes, such as ER-proRed, offer a sensitive and simplified tool for studying reticulophagy in biology and diseases.Abbreviations: Baf-A1, bafilomycin A1; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CQ, chloroquine diphosphate; ER, endoplasmic reticulum; FHR, fluorinated hydrophobic rhodol; GFP, green fluorescent protein; Reticulophagy, selective autophagy of ER; RFP, red fluorescent protein; ROX, X-rhodamine; UPR, unfolded protein response.
    Keywords:  Autophagy imaging; endoplasmic reticulum; fluorescence-on; lysosomal acidity; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2165759
  15. Trends Cell Biol. 2023 Jan 07. pii: S0962-8924(22)00277-X. [Epub ahead of print]
    ERASing endoplasmic reticulum stress: the faster, the better.
    Jogender Singh.
      The endoplasmic reticulum (ER) has evolved multiple mechanisms to maintain homeostasis under stress conditions. A recent study by Efstathiou et al. identified a novel mechanism of silencing ER-associated RNAs by the exogenous RNA interference pathway. This adaptive response reduces protein flux in the ER under stressful conditions.
    Keywords:  ERAD; RNA interference; RNA silencing; endoplasmic reticulum
    DOI:  https://doi.org/10.1016/j.tcb.2022.12.003
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