bims-unfpre 2025-01-12 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–01–12
eight papers selected by
Susan Logue, University of Manitoba

The interplay between gut microbiota and the unfolded protein response: Implications for intestinal homeostasis preservation and dysbiosis-related diseases.
A stress paradox: the dual role of the unfolded protein response in the placenta.
PERK Signaling Maintains Hematopoietic Stem Cell Pool Integrity under Endoplasmic Reticulum Stress by Promoting Proliferation.
Quercetin Alleviates All-Trans-Retinal-Induced Photoreceptor Apoptosis and Retinal Degeneration by Inhibiting the ER Stress-Related PERK Signaling.
Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells.
Noncanonical UPR factor CREB3L2 drives immune evasion of triple-negative breast cancer through Hedgehog pathway modulation in T cells.
Chemotherapy-Induced Cell-Surface GRP78 Expression as a Prognostic Marker for Invasiveness of Metastatic Triple-Negative Breast Cancer.
Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines.

Microb Pathog. 2025 Jan 04. pii: S0882-4010(25)00004-X. [Epub ahead of print]200 107279

The interplay between gut microbiota and the unfolded protein response: Implications for intestinal homeostasis preservation and dysbiosis-related diseases.

Miriam Di Mattia, Michele Sallese, Loris Riccardo Lopetuso.

  The unfolded protein response (UPR) is a complex intracellular signal transduction system that orchestrates the cellular response during Endoplasmic Reticulum (ER) stress conditions to reestablish cellular proteostasis. If, on one side, prolonged ER stress conditions can lead to programmed cell death and autophagy as a cytoprotective mechanism, on the other, unresolved ER stress and improper UPR activation represent a perilous condition able to trigger or exacerbate inflammatory responses. Notably, intestinal and immune cells experience ER stress physiologically due to their high protein secretory rate. Indeed, there is evidence of UPR's involvement in both physiological and pathological intestinal conditions, while less is known about its bidirectional interaction with gut microbiota. However, gut microbes and their metabolites can influence ER stress and UPR pathways, and, in turn, ER stress conditions can shape gut microbiota composition, with important implications for overall intestinal health. Thus, targeting UPR components is an intriguing strategy for treating ER stress-linked dysbiosis and diseases, particularly intestinal inflammation.

Keywords:  Autophagy; Immunity; KDEL receptors; Microbiota; Proteostasis

DOI:  https://doi.org/10.1016/j.micpath.2025.107279
Front Endocrinol (Lausanne). 2024 ;15 1525189

A stress paradox: the dual role of the unfolded protein response in the placenta.

Diba Chowdhury, Chloe E Jang, Patrick Lajoie, Stephen J Renaud.

  The placenta is a temporary organ that forms during pregnancy and is essential for fetal development and maternal health. As an endocrine organ, proper placental function requires continual production, folding, and transport of proteins and lipids. Central to these processes is the endoplasmic reticulum (ER), a dynamic organelle responsible for maintaining cellular protein and lipid synthesis and processing. ER stress occurs when there is an accumulation of unfolded or misfolded proteins, which triggers the activation of cellular pathways collectively called the unfolded protein response. Unfolded protein response pathways act to alleviate the misfolded protein burden and restore ER homeostasis, or if unresolved, initiate cell death. While prolonged ER stress has been linked to deficient placental function and adverse pregnancy outcomes, basal activation of unfolded protein response pathways is required for placental development and function. This review explores the importance of ER homeostasis in placental development and function, examining how disruptions in ER stress responses may contribute to adverse pregnancy outcomes.

Keywords:  ER stress; UPR; decidua; placenta; trophoblast

DOI:  https://doi.org/10.3389/fendo.2024.1525189
bioRxiv. 2024 Dec 17. pii: 2024.12.13.628451. [Epub ahead of print]

PERK Signaling Maintains Hematopoietic Stem Cell Pool Integrity under Endoplasmic Reticulum Stress by Promoting Proliferation.

Manxi Zheng, Qinlu Peng, Erin M Kropp, Zhejuan Shen, Suxuan Liu, Zhengyou Yin, Sho Matono, Takao Iwawaki, Xiang Wang, Ken Inoki, Yang Mei, Qing Li, Lu Liu.

The integrity of the hematopoietic stem cell (HSC) pool relies on efficient long-term self-renewal and the timely removal of damaged or differentiation-prone HSCs. Previous studies have demonstrated the PERK branch of the unfolded protein response (UPR) drives specific programmed cell death programs to maintain HSC pool integrity in response to ER stress. However, the role of PERK in regulating HSC fate in vivo remains unclear. Here, we demonstrate that PERK is dispensable for normal hematopoiesis and HSC self-renewal under steady-state conditions. In contrast, PERK is activated to promote HSC proliferation and depletion in response to ER stress induced by the inactivation of ER-associated degradation (ERAD), via the knockout of key components of ERAD Sel1L or Hrd1. Inhibition of PERK, either through genetic knockout or knock-in of a point mutation that eliminates PERK kinase activity, significantly restores the HSC defects induced by Sel1L or Hrd1 knockout. Mechanistic studies reveal that ERAD deficiency does not lead to HSC death or ROS accumulation. Instead, PERK promotes the activation of mTOR signaling and drives abnormal proliferation of HSCs, impairing their self-renewal potential. This process removes stressed HSCs, thereby maintaining HSC pool integrity. Our study uncovers a PERK-centered strategy employed by HSCs to preserve their pool integrity independently of apoptosis.
Key points: PERK is not required for steady-state hematopoiesis but preserves hematopoietic stem cell pool integrity in response to increased ER stress.Under ER stress induced by ERAD deficiency, PERK is activated to promote mTOR signaling and HSC hyper-proliferation, depleting damaged HSCs.

DOI: https://doi.org/10.1101/2024.12.13.628451
Int J Mol Sci. 2024 Dec 19. pii: 13624. [Epub ahead of print]25(24):

Quercetin Alleviates All-Trans-Retinal-Induced Photoreceptor Apoptosis and Retinal Degeneration by Inhibiting the ER Stress-Related PERK Signaling.

Bo Yang, Kunhuan Yang, Ruitong Xi, Jingmeng Chen, Yalin Wu.

  All-trans-retinal (atRAL)-induced photoreceptor atrophy and retinal degeneration are hallmark features of dry age-related macular degeneration (AMD) and Stargardt disease type 1 (STGD1). The toxicity of atRAL is closely related to the generation of reactive oxygen species (ROS). Quercetin, a natural product, is known for its potent antioxidant properties; however, its effects in mitigating atRAL-mediated retinal damage remains unclear. This study investigated the protective effects of quercetin against atRAL-induced photoreceptor damage. Using atRAL-loaded 661W photoreceptor cells, we evaluated cell viability, ROS generation, and endoplasmic reticulum (ER) stress under quercetin treatment. Quercetin significantly restored the cell viability (to 70%) and reduced ROS generation in atRAL-treated 661W cells. Additionally, Western blot analysis demonstrated that quercetin mitigated protein kinase RNA-like ER kinase (PERK) signaling, preventing ER stress-induced apoptosis. Importantly, in Abca4-/-Rdh8-/- mice, an animal model of light-induced atRAL accumulation in the retina, quercetin treatment effectively alleviated light-exposed photoreceptor atrophy and retinal degeneration by attenuating PERK signaling. Thus, quercetin protected photoreceptor cells from atRAL-induced damage by inhibiting ROS generation and PERK signaling, which suggests its potential as a therapeutic agent for atRAL-related retinal degeneration.

Keywords:  ER stress; all-trans-retinal; apoptosis; photoreceptor; quercetin

DOI:  https://doi.org/10.3390/ijms252413624
Nat Commun. 2025 Jan 09. 16(1): 524

Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells.

Li-Xian Yang, Chuangye Qi, Si Lu, Xiang-Shi Ye, Parnaz Merikhian, Du-Yu Zhang, Tao Yao, Jiang-Sha Zhao, Ying Wu, Yongshi Jia, Bo Shan, Jinghai Chen, Xiaozhou Mou, Jia You, Wenbo Li, Yu-Xiong Feng.

Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. Analysis of human data confirms a strong correlation between HSC ATF4 expression and liver fibrosis progression. Importantly, a small molecule inhibitor targeting ATF4 translation effectively mitigates liver fibrosis. Together, our findings identify a mechanism promoting liver fibrosis and reveal new opportunities for treating this otherwise non-targetable disease.

DOI: https://doi.org/10.1038/s41467-024-55738-1
Sci Adv. 2025 Jan 10. 11(2): eads5434

Noncanonical UPR factor CREB3L2 drives immune evasion of triple-negative breast cancer through Hedgehog pathway modulation in T cells.

Zi-Jian Cao, Jia You, Yu-Meng Fan, Jia-Ying Yang, Jirui Sun, Xiuli Ma, Jinku Zhang, Zhongwu Li, Xiang Wang, Yu-Xiong Feng.

The unfolded protein response (UPR) pathway is crucial for tumorigenesis, mainly by regulating cancer cell stress responses and survival. However, whether UPR factors facilitate cell-cell communication between cancer cells and immune cells to drive cancer progression remains unclear. We found that adenosine 3',5'-monophosphate response element-binding protein 3-like protein 2 (CREB3L2), a noncanonical UPR factor, is overexpressed and activated in triple-negative breast cancer, where its cleavage releases a C-terminal fragment that activates the Hedgehog pathway in neighboring CD8+ T cells. The enhanced Hedgehog pathway represses CD8+ T cell activation and inhibits its cytotoxic effects. Consequently, overexpression of CREB3L2 not only promotes tumor growth but also causes resistance to immune checkpoint blockade (ICB). Inhibition of the Hedgehog pathway impedes the growth of CREB3L2-overexpressed tumors and sensitizes them to ICB therapy. In summary, we identified a previously unidentified mechanism by which the UPR pathway dictates cross-talk between cancer cells and immune cells, providing important anticancer therapeutic opportunities.

DOI: https://doi.org/10.1126/sciadv.ads5434
Ann Biomed Eng. 2025 Jan 05.

Chemotherapy-Induced Cell-Surface GRP78 Expression as a Prognostic Marker for Invasiveness of Metastatic Triple-Negative Breast Cancer.

Martha B Alvarez-Elizondo, Annat Raiter, Rinat Yerushalmi, Daphne Weihs.

  Metastasis remains the leading cause (90%) of cancer-related mortality, especially in metastatic triple-negative breast cancer (TNBC). Improved understanding of molecular drivers in the metastatic cascade is crucial, to find accurate prognostic markers for invasiveness after chemotherapy treatment. Current breast cancer chemotherapy treatments include doxorubicin and paclitaxel, inducing various effects, such as the unfolded protein response (UPR). The key regulator of the UPR is the 78-kDa glucose-regulated protein (GRP78), which is associated with metastatic disease, although, its expression level in the context of invasiveness is still controversial. We evaluate doxorubicin effects on TNBC cells, identifying GRP78 subpopulations linked to invasiveness. Specifically, we evaluate the motility and invasiveness of GRP78 positive vs. negative cell subpopulations by two different assays: the in vitro Boyden chamber migration assay and our innovative, rapid (2-3 h) clinically relevant, mechanobiology-based invasiveness assay. We validate chemotherapy-induced increase in the subpopulation of cell-surface GRP78(+) in two human, metastatic TNBC cell lines: MDA-MB-231 and MDA-MB-468. The GRP78(+) cell subpopulation exhibits reduced invasiveness and metastatic potential, as compared to whole-population control and to the GRP78(-) cell subpopulation, which are both highly invasive. Thus, using our innovative, clinically relevant assay, we rapidly (on clinical timescale) validate that GRP78(-) cells are likely linked with invasiveness, yet also demonstrate that combination of the GRP78(+) and GRP78(-) cells could increase the overall metastatic potential. Our results and approach could provide patient-personalized predictive marker for the expected benefits of chemotherapy in TNBC patients and potentially reveal non-responders to chemotherapy while also allowing evaluation of the clinical risk for metastasis.

Keywords:  Cancer metastasis; Cell invasiveness; Chemotherapy resistance; Doxorubicin; Mechanobiology

DOI:  https://doi.org/10.1007/s10439-024-03673-z
Cells. 2024 Dec 15. pii: 2069. [Epub ahead of print]13(24):

Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines.

Helena Domínguez-Martín, Elena Gavilán, Celia Parrado, Miguel A Burguillos, Paula Daza, Diego Ruano.

  Autophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell types: the microglia-like cell line BV2 and the neuronal-like cell line N2a. Proteotoxic stress, induced by proteasome inhibition, produced early apoptosis in BV2 cells, due in part to a predominant activation of the PERK-CHOP pathway. In contrast, N2a cells showcased greater resistance and robust induction of the IRE1α-sXbp1 arm of the UPR. We also demonstrated that proteotoxic stress activated autophagy in both cell lines but with different kinetics and cellular functions. In N2a cells, autophagy restored cellular proteostasis, while in BV2 cells, it participated in regulating phagocytosis. Finally, proteotoxic stress predominantly activated the mTORC2-AKT-FOXO1-β-catenin pathway in BV2 cells, while N2a cells preferentially induced the PDK1-AKT-FOXO3 axis. Collectively, our findings suggest that proteotoxic stress triggers cell-specific responses in microglia and neurons, with different physiological outcomes.

Keywords:  autophagy; microglia; neurons; phagocytosis; proteasome; proteostasis; proteotoxic stress

DOI:  https://doi.org/10.3390/cells13242069