bims-unfpre 2025-02-02 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–02–02
six papers selected by
Susan Logue, University of Manitoba

ERMP1 as a newly identified ER stress gatekeeper in chronic kidney disease.
Molecular and therapeutic insight into ER Stress signaling in NSCLC.
GRP78: A New Promising Candidate in Colorectal Cancer Pathogenesis and Therapy.
An ER stress and mitochondrial apoptosis Co-inducer for enhanced cancer immunotherapy.
Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential.
Functionally diversified BiP orthologs control body growth, reproduction, stress resistance, aging, and ER-Phagy in Caenorhabditis elegans.

Am J Physiol Renal Physiol. 2025 Jan 28.

ERMP1 as a newly identified ER stress gatekeeper in chronic kidney disease.

Marta Correia de Sousa, Grégoire Arnoux, Raphaël Yvon, Christine Maeder, Margot Fournier, Noëlie Morin, Dobrochna Dolicka, Etienne Delangre, Miranda Türkal, Thibault Charlemagne, Sophie de Seigneux, David Legouis, Pierre Maechler, Eric Feraille, Michelangelo Foti, Monika Gjorgjieva.

  ERMP1 is involved in the Unfolded Protein Response (UPR) pathway in response to endoplasmic reticulum (ER) stress. Given the pivotal role of ER stress in the pathogenesis of acute and chronic kidney diseases, we hypothesized that ERMP1 could be instrumental in the development of renal injury. In silico analysis of RNA sequencing datasets from renal biopsies were exploited to assess the expression of ERMP1 in the kidney under normal or pathological conditions. CRISPR-Cas9- mediated heterozygous genetic ablation of the exon 1 of Ermp1 was performed in vivo, followed by histological analysis and assessment of renal injury and ER stress markers in the newly generated Ermp1 knockout mouse model. Additionally, knockdown and overexpression of ERMP1 were conducted in human tubular cells to investigate cell viability, metabolism, the UPR pathway and ER Ca2+ release under these conditions. Our findings from patient datasets showed that ERMP1 is expressed in all renal cell types and is upregulated in chronic kidney disease. Further in silico investigations suggest a role for ERMP1 in renal development. ERMP1 knockout in mice revealed that homozygous loss of ERMP1 expression is lethal, while heterozygous loss exacerbated age-related chronic kidney alteration. In human tubular cells, ERMP1 knockdown decreased viability and metabolic rate, whereas overexpression conferred protection against ER stress. These results highlight the importance of ERMP1 in renal physiology and pathology and suggest that its upregulation could be a protective mechanism against excessive ER stress in renal tubule epithelial cells.

Keywords:  ER stress; ERMP1; chronic kidney disease

DOI:  https://doi.org/10.1152/ajprenal.00159.2024
J Drug Target. 2025 Jan 30. 1-18

Molecular and therapeutic insight into ER Stress signaling in NSCLC.

Aastha Jadhav, Arjun Menon, Kush Gupta, Neeru Singh.

  Endoplasmic Reticulum (ER) stress is intricately involved in cancer development, progression and response to chemotherapy. ER stress related genes might play an important role in predicting the prognosis in lung adenocarcinoma patients and may be manipulated to improve the treatment outcome and overall survival rate. In this review, we analyzed the contribution of the three major ER stress pathways-IRE1, ATF6, and PERK-in lung cancer pathogenesis via modulation of tumor microenvironment (TME) and processes as metastasis, angiogenesis, apoptosis and N-glycosylation. Furthermore, we discuss the regulatory role of microRNAs in fine-tuning ER stress pathways in Non-Small Cell Lung Cancer (NSCLC). Our review also highlights various promising strategies to overcome chemoresistance by targeting ER stress pathways, offering new therapeutic opportunities.

Keywords:  ATF6; Chemoresistance; ER stress; IRE1; Non-Small Cell Lung Cancer (NSCLC); PERK; miRNA

DOI:  https://doi.org/10.1080/1061186X.2025.2461105
Eur J Pharmacol. 2025 Jan 25. pii: S0014-2999(25)00061-5. [Epub ahead of print] 177308

GRP78: A New Promising Candidate in Colorectal Cancer Pathogenesis and Therapy.

Wang Song, Neda Rahimian, Aysa Hasanzade Bashkandi.

  Colorectal cancer (CRC) is a significant global health challenge, marked by varying incidence and mortality rates across different regions. The pathogenesis of CRC involves multiple stages, including initiation, promotion, progression, and metastasis, influenced by genetic and epigenetic factors. The chaperone protein glucose-regulated protein 78 (GRP78), crucial in regulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, plays a pivotal role in CRC pathogenesis. This review discusses the expression profile of GRP78 in CRC, highlighting its potential as a prognostic biomarker and its role in modulating the cellular mechanisms of CRC, including ER response regulation, cell proliferation, migration and invasion. The complex molecular interactions of GRP78 with key signaling pathways such as protein kinase B (Akt), Wnt, protein kinase R-like ER kinase (PERK), vascular endothelial growth factor (VEGF), and Kirsten rat sarcoma virus (Kras) are explored, elucidating its contributions to tumor survival, proliferation, invasion, and chemoresistance. GRP78's involvement in autophagy, glycolysis, and immune regulation further underscores its importance in CRC progression. The review also covers the therapeutic potential of targeting GRP78 in CRC, examining various natural products like curcumin, epigallocatechin gallate (EGCG), and aloe-emodin, which modulate GRP78 expression and activity. Additionally, GRP78's role in mediating resistance to chemotherapeutic agents like 5-fluorouracil (5-FU) and oxaliplatin is discussed, emphasizing its significance in the development of resistance mechanisms in CRC. In conclusion, GRP78 emerges as a central player in CRC pathogenesis and a promising target for therapeutic interventions aimed at improving treatment outcomes and overcoming chemoresistance in colorectal cancer.

Keywords:  HSP70; Unfolded protein response; chaperones; colon cancer; endoplasmic reticulum stress; pharmacotherapy

DOI:  https://doi.org/10.1016/j.ejphar.2025.177308
Cancer Lett. 2025 Jan 22. pii: S0304-3835(25)00049-7. [Epub ahead of print]612 217485

An ER stress and mitochondrial apoptosis Co-inducer for enhanced cancer immunotherapy.

Guangzhao Xu, Shuzhen Chen, Hekai Yang, Xiaozhe Feng, Fahui Li, Huishuang Zhao, Le Sun, Ping Yan, Yuxi Chen, Guanhong Guo, Wen Sun, Weiguo Song, Zhe-Sheng Chen, Liuya Wei, Wenda Zhong.

  Though immunogenic cell death (ICD) has garnered significant attention in the realm of anticancer therapies, effectively stimulating strong immune responses with adequate antigen presentation in deep-seated cancers remains challenging. Herein, to promote antigen presentation, an efficient dual-targeted photodynamic ICD inducer is developed. Due to the enhanced spin-orbit coupling and electron structure modulation, the Cy5-I-CF3 probe showcases exceptional reactive oxygen species (ROS) generation capacity within cancer cells. The Cy5-I-CF3 also displays the co-targeting ability toward the endoplasmic reticulum (ER) and mitochondria. More importantly, the in-situ ROS generation synergistically facilitates the interaction between ER and mitochondria, thereby invoking a more robust ER stress response through cascade amplification mechanisms, resulting in substantial release of damage-associated molecular patterns (DAMPs) and strong induction of ICD. This augmentation ultimately enhances the endogenous antigen presentation machinery. Adequate antigen presentation promotes the dendritic cell (DC) maturation and infiltration of cytotoxic T lymphocytes (CTLs) to realize efficient immunotherapy. As a result, Cy5-I-CF3 notably restrains the growth of distant and primary cancers by photodynamic-induced immunotherapy. Our research offers valuable insights for the design of efficacious ICD inducers, advancing the utilization of cancer immunotherapy.

Keywords:  ER stress; Immunogenic cell death; Mitochondrial apoptosis; Photodynamic ROS generation; Synergistic effect

DOI:  https://doi.org/10.1016/j.canlet.2025.217485
Biochim Biophys Acta Mol Basis Dis. 2025 Jan 24. pii: S0925-4439(25)00040-7. [Epub ahead of print]1871(3): 167695

Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential.

Tiantian Wang, Guoqing Xia, Xue Li, Mingxu Gong, Xiongwen Lv.

  This paper reviews the important role of endoplasmic reticulum stress in the patho mechanism of liver fibrosis and its potential as a potential target for the treatment of liver fibrosis. Liver fibrosis is the result of sustained inflammation and injury to the liver due to a variety of factors, triggering excessive deposition of extracellular matrix and fibrous scar formation, which in turn leads to loss of liver function and a variety of related complications. Endoplasmic reticulum stress is one of the characteristics of chronic liver disease and is closely related to the pathological process of chronic liver disease, including alcohol-related liver disease, viral hepatitis, and liver fibrosis. The unfolded protein response is one of the important response mechanisms to endoplasmic reticulum stress. It is associated with several pathological aspects of liver fibrosis and the maintenance of endoplasmic reticulum homeostasis. Interventions targeting endoplasmic reticulum stress for the treatment of liver fibrosis have potential research and application value. An in-depth understanding of the biological basis of endoplasmic reticulum stress is also needed in the treatment of liver fibrosis, as well as the development of more effective drugs and interventions to accurately regulate the endoplasmic reticulum signaling network, to achieve the restoration and maintenance of endoplasmic reticulum homeostasis at the cellular and organ levels, and to further promote the reversal of the pathological process of liver fibrosis.

Keywords:  ATF6; ER stress; IRE1α; Liver fibrosis; PERK; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bbadis.2025.167695
bioRxiv. 2025 Jan 19. pii: 2025.01.14.633073. [Epub ahead of print]

Functionally diversified BiP orthologs control body growth, reproduction, stress resistance, aging, and ER-Phagy in Caenorhabditis elegans.

Nicholas D Urban, Shannon M Lacy, Kate M Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, Matthias C Truttmann.

Cellular systems that govern protein folding rely on a delicate balance of functional redundancy and diversification to maintain protein homeostasis (proteostasis). Here, we use Caenorhabditis elegans to demonstrate how both overlapping and divergent activities of two homologous endoplasmic reticulum (ER)-resident HSP70 family chaperones, HSP-3 and HSP-4, orchestrate ER proteostasis and contribute to organismal physiology. We identify tissue-, age-, and stress-specific protein expression patterns and find both redundant and distinct functions for HSP-3 and HSP-4 in ER stress resistance, reproduction, and body size regulation. We show that only HSP-3 overexpression is sufficient to improve longevity and that loss of HSP-3 or HSP-4 during distinct stages of the worm cycle or specific tissues have opposing effects on worm lifespan. Furthermore, we find that loss of HSP-4, but not HSP-3, improves tolerance to protein aggregation induced-stress by activating ER-Phagy through the engagement of IRE-1 and the putative ER-Phagy receptor, C18E9.2. Mechanistically, we show that de-repression of IRE-1 via HSP-4 dissociation allows for direct inhibition of C18E9.2- mediated ER-Phagy and demonstrate that a conserved orthologous mechanism involving the respective human orthologs, BiP, Sec-62, and IRE-1, contributes to ER proteostasis regulation in human cells. Taken as a whole, our study demonstrates that functional diversification of orthologous proteins within a single organelle is an efficient mechanism to maximize stress resilience while also defining a novel link between ER- phagy and proteostasis regulation.

DOI: https://doi.org/10.1101/2025.01.14.633073