bims-unfpre 2025-03-09 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–03–09
eight papers selected by
Susan Logue, University of Manitoba

A BiP-centric view of endoplasmic reticulum functions and of my career.
Alterations in ether phospholipids metabolism activate the conserved UPR-Xbp1- PDIA3/ERp60 signaling to maintain intestinal homeostasis.
When Proteins Go Berserk: The Unfolded Protein Response and ER stress.
Crucial roles of Grr1 in splicing and translation of HAC1 mRNA upon unfolded stress response.
Requirements for nuclear GRP78 transcriptional regulatory activities and interaction with nuclear GRP94.
An unfolded protein response (UPR)-signature regulated by the NFKB-miR-29b/c axis fosters tumor aggressiveness and poor survival in bladder cancer.
CHOP aggravates hepatocyte apoptosis upon endoplasmic reticulum stress by down-regulating autophagy.
Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.

J Mol Biol. 2025 Feb 28. pii: S0022-2836(25)00118-4. [Epub ahead of print] 169052

A BiP-centric view of endoplasmic reticulum functions and of my career.

Linda M Hendershot.

  After completing my post-doctoral training at the University of Alabama, Birmingham and a brief period on the faculty there, I joined the Department of Tumor Cell Biology at St. Jude Children's Research Hospital in 1987 as an Assistant Member and started my independent research program. For the following 37 years, I led a relatively small basic research group comprised at various times of post-doctoral fellows, graduate students, undergraduate students, and research technicians; many of whom I am still in contact. Last year I closed the lab and transitioned to an emeritus position at St. Jude. I continue to maintain several research collaborations covering areas of research that have long been dear to my heart. My post-doctoral studies on BiP revealed that it controlled immunoglobulin assembly and transport, and as such, played a critical role in fidelity of the immune response. My lab continued to define BiP's functions in protein folding and subunit assembly, as well as, in degradation using biochemical, cell-based, and biophysical analyses. Several ER localized co-factors that regulate the activity of BiP and allow it to contribute to its multiple ER functions were identified by our group. These include DnaJ family members and nucleotide change factors. Through a variety of collaborative studies, we pursued BiP's functions in maintaining the permeability barrier of the translocon, contributing to ER calcium stores, and regulating the up-stream transducers of the UPR, a stress response that is activated by the accumulation of unfolded proteins in the ER.

Keywords:  ER stress; Endoplasmic Reticulum; Immunoglobulins; Molecular chaperones; Quality Control of Protein Maturation; Secretory pathway protein biosynthesis; UPR

DOI:  https://doi.org/10.1016/j.jmb.2025.169052
iScience. 2025 Mar 21. 28(3): 111946

Alterations in ether phospholipids metabolism activate the conserved UPR-Xbp1- PDIA3/ERp60 signaling to maintain intestinal homeostasis.

Stephanie Makdissi, Rihab Loudhaief, Smitha George, Tabatha Weller, Minna Salim, Ahsan Malick, Yizhu Mu, Brendon D Parsons, Francesca Di Cara.

  Intestinal epithelium regeneration and homeostasis must be tightly regulated. Alteration of epithelial homeostasis is a major contributing factor to diseases such as colorectal cancer and inflammatory bowel diseases. Many pathways involved in epithelial regeneration have been identified, but more regulators remain undiscovered. Metabolism has emerged as an overlooked regulator of intestinal epithelium homeostasis. Using the model organism Drosophila melanogaster, we found that ether lipids metabolism is required to maintain intestinal epithelial homeostasis. Its dysregulation in intestinal progenitors causes the activation of the unfolded protein response of the endoplasmic reticulum (UPR) that triggers Xbp1 and upregulates the conserved disulfide isomerase PDIA3/ERp60. Activation of the Xbp1-ERp60 signaling causes Jak/Stat-mediated increase in progenitor cells, compromising epithelial barrier function and survival in males but not females. This study identified ether lipids-PDIA3/ERp60 as a key regulator of intestinal progenitor homeostasis in health that, if altered, causes pathological conditions in the intestinal epithelium.

Keywords:  Cell biology; Lipidomics; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.111946
Nephron. 2025 Mar 04. 1-14

When Proteins Go Berserk: The Unfolded Protein Response and ER stress.

Doria Meiseles, Narkis Arbeli, Moran Dvela-Levitt.

Background The cellular proteostasis machinery is essential for maintaining protein homeostasis by employing quality control systems that identify, sequester, and eliminate damaged or misfolded proteins. However, the accumulation of misfolded proteins can overwhelm these protective mechanisms, disrupting proteostasis. This phenomenon is a hallmark of numerous pathologies, including a variety of genetic disorders. In the secretory pathway, the buildup of misfolded proteins triggers endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). The UPR serves as an adaptive mechanism, aiming to alleviate stress and restore cellular homeostasis. However, if ER stress is prolonged or severe, the UPR may fail to restore balance and apoptosis is induced. Summary This review introduces the intricate signaling pathways activated by the three UPR transmembrane sensors: protein-kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). We briefly present the roles of the distinct transcriptional programs activated by each sensor in modulating the cellular response to protein stress and in determining cell fate. We discuss how genetic variants and environmental factors contribute to the heterogeneity observed in protein misfolding diseases. Finally, we critically evaluate select therapeutic strategies, specifically protein stabilization, trafficking modulation, and UPR sensor targeting approaches. Key message This review introduces the potential consequences of protein misfolding, which may not only impair protein function, but can also lead to toxic protein accumulation and stress induction. Using Fabry disease as a compelling example, we suggest that future therapeutic intervention may require nuanced, combination approaches that address both loss and gain of protein function.

DOI: https://doi.org/10.1159/000544971
Nat Commun. 2025 Mar 04. 16(1): 2172

Crucial roles of Grr1 in splicing and translation of HAC1 mRNA upon unfolded stress response.

Nichika Sato, Yu Nakano, Yasuko Matsuki, Shota Tomomatsu, Sihan Li, Yoshitaka Matsuo, Toshifumi Inada.

In the process of the unfolded protein response (UPR), the Hac1p protein is induced through a complex regulation of the HAC1 mRNA. This includes the mRNA localization on the endoplasmic reticulum (ER) membrane and stress-triggered splicing. In yeast, a specific ribosome ubiquitination process, the monoubiquitination of eS7A by the E3 ligase Not4, facilitates the translation of HAC1i, a spliced form of the HAC1 mRNA. Upon UPR, the mono-ubiquitination of eS7A increases due to the downregulation of Ubp3, a deubiquitinating enzyme of eS7A. However, the exact mechanisms behind these regulations have remained unknown. In this study, an E3 ligase, Grr1, an F-box protein component of the SCF ubiquitin ligase complex, which is responsible for Ubp3 degradation, has been identified. Grr1-mediated Ubp3 degradation is required to maintain the level of eS7A monoubiquitination that facilitates Hac1p translation depending on the ORF of HAC1i. Grr1 also facilitates the splicing of HAC1u mRNA independently of Ubp3 and eS7A ubiquitination. Finally, we propose distinct roles of Grr1 upon UPR, HAC1u splicing, and HAC1i mRNA translation. Grr1-mediated Ubp3 degradation is crucial for HAC1i mRNA translation, highlighting the crucial role of ribosome ubiquitination in translational during UPR.

DOI: https://doi.org/10.1038/s41467-025-57360-1
J Biol Chem. 2025 Feb 28. pii: S0021-9258(25)00218-2. [Epub ahead of print] 108369

Requirements for nuclear GRP78 transcriptional regulatory activities and interaction with nuclear GRP94.

Ze Liu, Dat P Ha, Liangguang Leo Lin, Ling Qi, Amy S Lee.

  GRP78, a molecular chaperone primarily located in the endoplasmic reticulum (ER), has recently been discovered to translocate into the nucleus of stressed and cancer cells where it assumes a new function reprogramming the transcriptome. This study explores the requirements of GRP78 nuclear translocation and its transcriptional activity and investigates the role of ER-associated degradation (ERAD) in the process. We show that the ER-processed, mature form of GRP78 is the major form of nuclear GRP78 and is the form with transcriptional regulatory activity. In contrast, exogenously expressed GRP78 designed to lack its ER signal peptide, thus preventing it from entering the ER or undergoing any ER-related processing/modification, while able to enter the nucleus, lacks transcriptional regulatory activity towards E-Box containing target genes. Additionally, the ATP-binding and substrate-binding activities of GRP78 are critical for this transcriptional regulatory function. We further discover that GRP94, an ER chaperone that acts in concert with GRP78 on protein folding, can translocate to the nucleus and co-localize with nuclear GRP78 upon ER stress. These findings suggest that some form of ER processing of GRP78, in addition to cleavage of the ER signal peptide, is critical for its nuclear activity and that in stressed cells, ER chaperones may assume new functions in the nucleus yet to be explored.

Keywords:  ER stress; ERAD; GRP78; GRP94; ID2; nuclear translocation; transcriptional regulation

DOI:  https://doi.org/10.1016/j.jbc.2025.108369
Front Mol Biosci. 2025 ;12 1542650

An unfolded protein response (UPR)-signature regulated by the NFKB-miR-29b/c axis fosters tumor aggressiveness and poor survival in bladder cancer.

Jian Zhang, Xiaosong Fan, Yu Chen, Yichao Han, Weixing Yu, Shaolin Zhang, Bicheng Yang, Junlong Zhang, Yanling Chen.

   Background: Bladder cancer continues to pose a substantial global health challenge, marked by a high mortality rate despite advances in treatment options. Therefore, in-depth understanding of molecular mechanisms related to disease onset, progression, and patient survival is of utmost importance in bladder cancer research. Here, we aimed to investigate the underlying mechanisms using a stringent differential expression and survival analyses-based pipeline.
Methods: Gene and miRNA expression data from TCGA and NCBI GEO databases were analyzed. Differentially expressed genes between normal vs tumor, among tumor aggressiveness groups and between early vs advanced stage were identified using Student's t-test and ANOVA. Kaplan-Meier survival analyses were conducted using R. Functional annotation, miRNA target and transcription factor prediction, network construction, random walk analysis and gene set enrichment analyses were performed using DAVID, miRDIP, TransmiR, Cytoscape, Java and GSEA respectively.
Results: We identified elevated endoplasmic reticulum (ER) stress response as key culprit, as an eight-gene unfolded protein response (UPR)-related gene signature (UPR-GS) drives aggressive disease and poor survival in bladder cancer patients. This elevated UPR-GS is linked to the downregulation of two miRNAs from the miR-29 family (miR-29b-2-5p and miR-29c-5p), which can limit UPR-driven tumor aggressiveness and improve patient survival. At further upstream, the inflammation-related NFKB transcription factor inhibits miR-29b/c expression, driving UPR-related tumor progression and determining poor survival in bladder cancer patients.
Conclusion: These findings highlight that the aberrantly activated UPR, regulated by the NFKB-miR-29b/c axis, plays a crucial role in tumor aggressiveness and disease progression in bladder cancer, highlighting potential targets for therapeutic interventions and prognostic markers in bladder cancer management.

Keywords:  ER stress; NFkB; UPR; bladder cancer; inflammation; miR-29b/c

DOI:  https://doi.org/10.3389/fmolb.2025.1542650
Cell Stress Chaperones. 2025 Feb 27. pii: S1355-8145(25)00011-2. [Epub ahead of print]

CHOP aggravates hepatocyte apoptosis upon endoplasmic reticulum stress by down-regulating autophagy.

Jia-Yu Wu, Bing Han, Ting Yang, Lu Zheng, Yi-Xin Guo, Jia-Yao Li, Xiao-Yu Guo, Huan-Huan Yin, Ru-Jia Xie.

   BACKGROUND: Endoplasmic reticulum (ER) stress-associated apoptosis is involved in various liver diseases, including liver fibrosis, nonalcoholic fatty liver disease, and cirrhosis. Hepatocytes respond to ER stress by eliciting unfolded protein response (UPR) and enhancing autophagy. Autophagy is a pivotal mechanism for sustaining normal ER function, through degradation of damaged ER fragments and removal of abnormal protein aggregates in the ER lumen. Failure to restore ER homeostasis via autophagy is harmful to hepatocytes and contributes to ER stress-associated apoptosis. Recent findings indicated that C/EBP homologous protein (CHOP) could exacerbate ER stress-related apoptosis by down-regulating autophagy, but the underlying mechanism remains elusive.
AIM: To investigate the impact of CHOP on ER stress-induced apoptosis in rat hepatocytes, and the potential molecular mechanisms.
METHODS: BRL-3A cells were pre-treated with rapamycin (RAP) and 3-methyladenine, then treated with dithiothreitol (DTT). Growth and apoptotic rates were detected using real-time cellular analysis (RTCA) and flow cytometry, respectively. ER stress-associated molecule levels were determined via western blotting. CHOP, small interfering RNA, and the lentivirus vector system were used to transfect BRL-3A cells and observe the impact of CHOP gene silencing or overexpression on autophagy and apoptosis. Chromatin immunoprecipitation (ChIP) was used to confirm whether CHOP binds directly to ATG12, ATG5, and LC3 promotor regions undergoing ER stress.
RESULTS: ER stress-associated molecules were dramatically upregulated in BRL-3A hepatocytes and hepatocyte apoptosis was augmented. RAP pre-treatment significantly reduced DTT-induced expression of ER stress-associated molecules; conversely, 3-MA pre-treatment promoted DTT-induced levels of ER stress-associated apoptotic molecules. Following the decreased CHOP expression in hepatocytes, the level of autophagy-associated molecules dramatically increased, and DTT-induced hepatocyte apoptosis decreased. However, opposite trends were observed in CHOP overexpression cells. A negative regulation of CHOP on autophagy-associated molecules including ATG12, ATG5, and LC3 in BRL-3A cells upon DTT treatment was detected via ChIP.
CONCLUSION: CHOP enhancement during ER stress inhibits autophagy and promotes hepatocyte apoptosis; however, the decreased CHOP gene expression could attenuate DTT-induced hepatocyte apoptosis. Overexpression of CHOP could aggravate DTT-induced hepatocyte apoptosis.

Keywords:  Apoptosis; Autophagy; C/EBP homologous protein; Endoplasmic reticulum stress; Hepatocyte

DOI:  https://doi.org/10.1016/j.cstres.2025.02.005
Cancer Med. 2025 Mar;14(5): e70684

Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.

Chaosheng Peng, Juan Wang, Shu Wang, Yan Zhao, Haoyuan Wang, Yuhao Wang, Yuxuan Ma, Jianjun Yang.

   BACKGROUND: The endoplasmic reticulum (ER) serves as a crucial hub for protein synthesis and processing, playing an essential role in maintaining protein homeostasis. Perturbations, such as hypoxia, oxidative stress, inadequate amino acid supply, Ca2+ imbalance, and acidosis, can disrupt cellular equilibrium and result in the accumulation of misfolded/unfolded proteins within the ER lumen. This triggers ER stress. In response to this stress, an unfolded protein response (UPR) is activated as a mechanism to cope with the stress and restore internal balance. The UPR is regulated by three sensors located in the ER: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). However, the UPR can promote tumor growth in vivo by affecting tumor angiogenesis, cell migration, cell metabolism, and treatment resistance, and has a huge impact on the tumor microenvironment.
MATERIALS AND METHODS: We conducted a literature review of scientific papers on the topic of ER stress in the tumor microenvironment.
RESULTS AND DISCUSSION: This review focuses on the inducing factors of ER stress, the mechanism of the UPR signaling pathway induced by ER stress, and the effect of ER stress on the tumor microenvironment and immune-infiltrating cells. Tumors can regulate their evolution by affecting themselves and the tumor microenvironment through endoplasmic reticulum stress. This study reveals the important role of endoplasmic reticulum stress in the occurrence and development of tumors, and provides new ideas and potential therapeutic targets for the precision treatment of tumors. Future studies can further explore the molecular mechanism of ER stress regulating tumor microenvironment and explore its application potential in clinical diagnosis and treatment.

Keywords:  endoplasmic reticulum stress; tumor microenvironment; unfolded protein response

DOI:  https://doi.org/10.1002/cam4.70684