bims-unfpre 2025-08-10 papers

Issue of 2025–08–10
eight papers selected by
Susan Logue, University of Manitoba

Cell Cycle. 2025 Aug 07. 1-31

Unfolded protein response complexity in gynecological tumor dynamics: therapeutic challenges and future perspectives.

Vandana Yadav, Aruna Sivaram, Renu Vyas.

Cancer cells frequently undergo stresses like hypoxia, glucose deprivation, and calcium depletion, leading to protein misfolding and accumulation of unfolded proteins in the ER, which trigger ER stress. The unfolded protein response (UPR) is activated by endoplasmic reticulum (ER) stress to restore protein homeostasis by regulating protein synthesis and degradation. This review explores the multifaceted role of UPR in tumor growth, chemoresistance, and immune evasion in gynecological cancers, particularly ovarian, endometrial, and cervical cancers. UPR-associated genes have been reported to have a potential role as disease biomarkers and therapeutic targets, thus improving early detection and personalized treatment. This review aims to give insights into the role of UPR pathway in gynecological cancers and offers new perspectives for future research and clinical applications.

Keywords: Unfolded protein response; biomarkers; chemoresistance; gynaecological cancers; immune modulation; therapeutic target

DOI: https://doi.org/10.1080/15384101.2025.2543091

Plant Physiol Biochem. 2025 Jul 31. pii: S0981-9428(25)00849-6. [Epub ahead of print]228 110321

IRE1 coordinates UPR and ERAD pathways to maintain protein homeostasis under ER stress in Arabidopsis.

Jae Yong Yoo, Ha Na Choi, Ki Seong Ko, Wahyu Indra Duwi Fanata, Rikno Harmoko, Sun Ho Kim, Jong Chan Hong, Sang-Kyu Lee, Woo Sik Chung, Kyun Oh Lee.

Environmental stress in plants often leads to the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), triggering the unfolded protein response (UPR) and ER-associated degradation (ERAD) to restore protein homeostasis. In Arabidopsis, the ER stress sensor IRE1 catalyzes the unconventional splicing of bZIP60 mRNA, producing a transcription factor that regulates UPR-related genes. However, the role of IRE1 in ERAD regulation remains unclear. Here, we demonstrate that ire1a&b double mutants show delayed induction of key ERAD components, including HRD1B, EBS5/HRD3, and EBS6/OS9, under tunicamycin-induced ER stress. In a genetic background carrying the misfolded brassinosteroid receptor Bri1-5, loss of IRE1 exacerbates dwarfism and increases the stability of Bri1-5 protein, indicating impaired ERAD activity. Overexpression of Bri1-5 in the ire1a&b background phenocopied the dwarf and stress-sensitive traits, confirming the role of IRE1 in mitigating ERAD substrate accumulation. Chemical inhibition experiments further revealed that proper glycoprotein processing and degradation are essential for normal growth and stress tolerance, and that IRE1 function is critical for coordinating these processes. Our findings uncover a key regulatory function of IRE1 in linking the UPR and ERAD pathways, thereby maintaining ER homeostasis and supporting plant growth under stress conditions.

Keywords: Arabidopsis; Bri1-5; Dwarfism; Endoplasmic reticulum stress; IRE1

DOI: https://doi.org/10.1016/j.plaphy.2025.110321

FASEB J. 2025 Aug 15. 39(15): e70905

UFMylation of BiP/GRP78 Is Crucial for Maintenance of Endoplasmic Reticulum Homeostasis.

Zhu Li, Qian Liang, Yanmin Guo, Yaxiang Wang, Miao Wang, Yu-Sheng Cong.

UFMylation is essential for the embryonic development of metazoans and is associated with several human diseases. Accumulating evidence indicates that the UFMylation pathway plays a critical role in the maintenance of endoplasmic reticulum (ER) homeostasis. However, the underlying mechanisms and relevant cellular targets remain largely unknown. Here, we report that the ER chaperone protein BiP can be covalently modified by UFM1 at lysine residues 294, 296, 352, 353, and 370. This modification destabilizes BiP by promoting its ubiquitination and subsequent proteasome degradation. Depletion of the UFM1 E3 ligase UFL1 or mutation of the BiP UFMylation sites impairs BiP's functions as an ER chaperone and ER stress sensor, thereby increasing apoptotic cell death under ER stress. Our findings suggest that the UFMylation of BiP is critical for maintaining ER homeostasis.

Keywords: BiP; ER homeostasis; UFL1; UFMylation; UPR

DOI: https://doi.org/10.1096/fj.202500976RR

Diabetes. 2025 Aug 04. pii: db250405. [Epub ahead of print]

ALY688 Attenuates Iron-Induced ER Stress and Insulin Resistance via Activation of ER-Phagy.

Khang Nguyen, Jialing Tang, Damian Gatica, Ryan C Russell, Hye Kyoung Sung, Gary Sweeney.

ARTICLE HIGHLIGHTS: This study adds mechanistic insight to the association between excess iron and insulin resistance and identifies an effective intervention strategy. Using a cellular skeletal muscle cell model and a preclinical animal model, we show that iron elicits endoplasmic reticulum (ER) stress and impairs insulin signaling. The adiponectin receptor agonist peptide ALY688 counteracts iron-induced ER stress and maintains insulin sensitivity. Loss-of-function approaches indicated that ALY688 acts via an autophagy-dependent, and specifically ER-phagy-dependent, mechanism.

DOI: https://doi.org/10.2337/db25-0405

Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2503115122

Time-resolved photocatalytic proximity labeling uncovers ER proteome dynamics underlying UPR-to-apoptosis transition.

Nan Zhou, Yan Zhang, Peng R Chen, Xinyuan Fan.

Apoptosis is a critical outcome of stress-induced processes, with the endoplasmic reticulum (ER) playing a central role in apoptotic protein processing and stress signal transduction. Profiling the ER proteome during stress to cell death offers valuable insights into these processes, but existing methods often suffer from a loss of in situ information or requirement of genetic manipulation. In this study, we introduce CAT-ER, a nongenetic ER proteomics system that provides in situ labeling, spatiotemporal resolution, and compatibility across diverse cell types. By combining an ER-targeted iridium photocatalyst with a thio-quinone methide (thioQM) probe, CAT-ER achieves high specificity in enriching ER proteins, comparable to traditional enzymatic methods. Importantly, CAT-ER is free of genetic manipulation, allowing its use in hard-to-transfect cell types like HeLa and immune cells (e.g., Raji, Jurkat, and RAW264.7). Given the high spatiotemporal resolution of CAT-ER, we revealed dynamic ER proteome changes during thapsigargin (Tg)-induced unfolded protein response (UPR) to apoptosis. Notably, NFIP2 mitigated ER stress by halting translation when UPR initiated, while compromised EMC2 delayed apoptosis during prolonged stress. These findings provide insights into the molecular dynamics linking the UPR and apoptosis. Collectively, CAT-ER serves as a versatile tool for spatiotemporal proteomic analysis without the need for genetic manipulation, offering a powerful approach to study ER dynamics in various biological contexts.

Keywords: apoptosis; endoplasmic reticulum; proximity labeling; subcellular proteomics; unfolded protein response

DOI: https://doi.org/10.1073/pnas.2503115122

bioRxiv. 2025 Jul 21. pii: 2025.07.16.665212. [Epub ahead of print]

Optogenetic Clustering of Human IRE1 Reveals Differential Regulation of Transcription and mRNA Splice Isoform Abundance by the UPR.

Jacob W Smith, Damien B Wilburn, Vladislav Belyy.

Inositol-requiring enzyme 1 (IRE1) is one of three known sensor proteins that respond to homeostatic perturbations in the metazoan endoplasmic reticulum. The three sensors collectively initiate an intertwined signaling network called the Unfolded Protein Response (UPR). Although IRE1 plays pivotal roles in human health and development, understanding its specific contributions to the UPR remains a challenge due to signaling crosstalk from the other two stress sensors. To overcome this problem, we engineered a light-activatable version of IRE1 and probed the transcriptomic effects of IRE1 activity in isolation from the other branches of the UPR. We demonstrate that 1) oligomerization alone is sufficient to activate IRE1 in human cells, 2) IRE1's transcriptional response evolves substantially under prolonged activation, and 3) the UPR induces major changes in mRNA splice isoform abundance in an IRE1-independent manner. Our data reveal previously unknown targets of IRE1 transcriptional regulation and direct degradation. Additionally, the tools developed here will be broadly applicable for precise dissection of signaling networks in diverse cell types, tissues, and organisms.

DOI: https://doi.org/10.1101/2025.07.16.665212

Autophagy. 2025 Aug 08. 1-16

GSTK1 and RETREG1/FAM134B-mediated reticulophagy attenuates tubular injury in diabetic nephropathy through endoplasmic reticulum stress and apoptosis.

Shumin Zhang, Wei Chen, Wenpeng Wang, Yifei Liu, Chanyue Zhao, Kexin Yang, Wenni Dai, Yanglei Ou, Xiangxiang Yin, Yangjun Long, Yu Liu, Lei Zhang, Lin Sun, Fuyou Liu, Li Xiao.

Reticulophagy is a key process to recovery from endoplasmic reticulum (ER) stress and for maintaining ER homeostasis by selectively removing damaged ER and its components. However, its precise mechanisms in diabetic nephropathy (DN) remain unclear. Here, we found that the expression of RETREG1/FAM134B (reticulophagy regulator 1) was decreased in the tubular cells in DN patients and animal models, which was positively correlated with estimated glomerular filtration rate (eGFR) and negatively associated with tubulointerstitial damage. Proximal tubule-specific knockout of Retreg1 exacerbated reticulophagy abnormalities in diabetic mice induced by high-fat diet (HFD) combined with streptozotocin (STZ), which was accompanied by increased ER stress, apoptosis of tubular cells and tubulointerstitial fibrosis. In vitro, overexpression of RETREG1 notably restored reticulophagy, and alleviated ER stress and apoptosis in HK-2 cells, a human proximal tubular cell line, treated with high glucose. Mechanistically, immunoprecipitation coupled with mass spectrometry (IP-MS) suggested that RETREG1 could interact with GSTK1 (glutathione s-transferase kappa 1). Silencing of GSTK1 further aggravated the reduction of reticulophagy and tubular injury both in vivo and in vitro. These effects in in vitro were partially blocked by overexpressing RETREG1. Collectively, these findings suggest that GSTK1 and RETREG1 exert a protective role in tubular injury through restoring reticulophagy and mitigating ER stress of tubular cells in DN.Abbreviation: ACTB: actin beta; cCASP3: cleaved caspase 3; CANX: calnexin; CASP: caspase; Co-IP: co-immunoprecipitation; DDIT3: DNA damage-inducible transcript 3; DN: diabetic nephropathy; ER: endoplasmic reticulum; FN1: fibronectin 1; GSTK1: glutathione S-transferase kappa 1; HFD: high-fat diet; HG: high glucose; HK-2: human tubular cell; HSPA5: heat shock protein family A (Hsp70) member 5; IHC: immunohistochemistry; IF: immunofluorescence; IP MS: immunoprecipitation coupled with mass spectrometry; LIR: LC3-interacting region; LTL: Lotus tetragonolobus lectin; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PACS2: phosphofurin acidic cluster sorting protein 2; PTCs: proximal tubular cells; PT: proximal tubule; RETREG1/FAM134B: reticulophagy regulator 1; RHD: reticulon homology domain; RT-qPCR: real time-quantitative PCR; SQSTM1/p62: sequestosome 1; STZ: streptozotocin; TECs: tubular epithelial cells; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UACR: urine albumin creatine ratio; UPR: unfolded protein response.

Keywords: Diabetic nephropathy; DsbA-L; ER homeostasis; FAM134B; reticulophagy/ER-phagy, tubular epithelial cells

DOI: https://doi.org/10.1080/15548627.2025.2541385

EMBO Mol Med. 2025 Aug 05.

Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.

Curran Landry, James P Costanzo, Miguel Mitne-Neto, Mayana Zatz, Ashleigh E Schaffer, Maria Hatzoglou, Alysson R Muotri, Helen C Miranda.

Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.

Keywords: ALS (Amyotrophic Lateral Sclerosis); ER-MAM (Endoplasmic Reticulum Mitochondria Associated Membrane); ISR (Integrated Stress Response); Neurodegeneration; VAPB ((Vesicle Associated Membrane Protein Associated Protein B)

DOI: https://doi.org/10.1038/s44321-025-00279-3