bims-unfpre 2026-07-19 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–07–19
eight papers selected by
Susan Logue, University of Manitoba

Leucine rich repeat containing protein 8B (LRRC8B) - A novel modulator of endoplasmic reticulum (ER) stress response.
The E3 ligase TRIM13 restrains LPS-induced inflammation by reducing STIM1 abundance and the IRE1α-dependent unfolded protein response.
Endoplasmic reticulum stress and apoptosis-associated biomarkers in rheumatoid arthritis: an exploratory case-control study.
Induction of paraptotic cell death in breast cancer cells by an iron chelator involved activation of UPR/MAPK pathway and inactivation of PI3K/AKT/mTOR.
ER quality control: how cells detoxify their own membrane from lipid stress.
Cell-type-specific ATF6α programs regulate epithelial mitochondrial homeostasis and pericyte remodeling during physiological and exposure-accelerated lung aging.
Developmental priming of adult proteostasis and longevity by NuA4 complex activity in early life.
The unfolded protein sensor IRE1 is essential for homeostatic dendritic cell maturation.

Biochim Biophys Acta Mol Cell Res. 2026 Jul 17. pii: S0167-4889(26)00094-7. [Epub ahead of print] 120195

Leucine rich repeat containing protein 8B (LRRC8B) - A novel modulator of endoplasmic reticulum (ER) stress response.

N Raja Mathanki, Olivia Neibel Isaac Newton, Amal Kanti Bera.

  The endoplasmic reticulum (ER), a major calcium ion (Ca2+) reservoir, plays a pivotal role in lipid synthesis, protein synthesis, and secretion. Disruption of ER function leads to the accumulation of misfolded proteins, resulting in ER stress. To restore cellular homeostasis, the unfolded protein response (UPR) is activated. However, prolonged or irreversible ER stress can trigger apoptosis and cell death. Cellular dysfunction and apoptosis arising from disrupted ER Ca2+ homeostasis are often implicated in neurodegenerative and metabolic disorders. We investigated the role of LRRC8B, an ER-resident protein previously linked to ER Ca2+ homeostasis, in the ER stress response. LRRC8B expression was upregulated in response to chemically induced ER stress. Overexpression of LRRC8B enhanced the viability of HEK293T cells exposed to the ER stressor tunicamycin, whereas LRRC8B knockdown increased their susceptibility to apoptosis. Furthermore, LRRC8B overexpression reduced protein aggregation during ER stress by upregulating cytoprotective genes associated with the adaptive UPR, including BiP, calnexin, and PDI. Conversely, LRRC8B knockdown decreased BiP expression and elevated the levels of ER stress-induced apoptotic proteins such as CHOP, Bax, and cleaved caspase-3. Co-treatment with the chemical chaperone, 4-PBA, partially rescued the LRRC8B knockdown cells undergoing apoptosis. In Neuro 2a (N2a) cells, LRRC8B overexpression diminished the aggregation of mutant huntingtin protein (HTT-83Q), associated with Huntington's disease, whereas its knockdown exacerbated HTT-83Q aggregation. Taken together, these findings suggest that LRRC8B is a key modulator of the ER stress response and plays a cytoprotective role.

Keywords:  ER stress; LRRC8B; Protein aggregation; Tunicamycin; UPR

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120195
Sci Signal. 2026 Jul 14. 19(946): eaeb2470

The E3 ligase TRIM13 restrains LPS-induced inflammation by reducing STIM1 abundance and the IRE1α-dependent unfolded protein response.

Zheng Li, Xuelian Li, Zhou Yu, Qian Fang, Tong Xia, Jiaying Huang, Mingjin Yang, Taoyong Chen.

Recognition of the bacterial product lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) initiates inflammatory responses. The unfolded protein response (UPR) elicited by endoplasmic reticulum (ER) stress can strengthen TLR4-dependent inflammatory responses. Here, we report that the ER-localized E3 ubiquitin ligase TRIM13 restrained LPS-induced inflammatory responses in macrophages and in mice by protecting the cells from ER stress. TRIM13 mediated Lys33-linked polyubiquitylation of the ER-localized Ca2+ sensor STIM1, promoting its degradation. TRIM13 deficiency caused STIM1 accumulation and activated store-operated Ca2+ entry (SOCE) and the inositol-requiring enzyme 1 α (IRE1α) branch of the UPR. Suppressing SOCE, chelating extracellular Ca2+, relieving ER stress, or blocking IRE1α activation inhibited the amplification of inflammatory responses caused by the loss of TRIM13 in macrophages. Pharmacological inhibition of IRE1α ameliorated chemically induced colitis in TRIM13-deficient mice. Our study suggests that TRIM13 restrains inflammation by limiting LPS-induced activation of SOCE and the IRE1α branch of the UPR.

DOI: https://doi.org/10.1126/scisignal.aeb2470
Rheumatol Int. 2026 Jul 14. pii: 202. [Epub ahead of print]46(8):

Endoplasmic reticulum stress and apoptosis-associated biomarkers in rheumatoid arthritis: an exploratory case-control study.

Burcu Yılmaz Isık, Arif Babayigit, Halef Okan Dogan, Ali Sahin.

  Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction, leading to functional disability and reduced quality of life. Beyond classical inflammatory pathways, increasing evidence indicates that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) contribute to immune dysregulation and chronic inflammation in RA. However, the clinical relevance of circulating ER stress-related biomarkers in RA remains insufficiently defined. This study aimed to evaluate serum levels of ER stress-related and apoptosis-associated markers in patients with RA, to assess their ability to discriminate RA from healthy individuals, and to explore their associations with inflammatory parameters and disease activity. This observational case-control study was conducted between 2021 and 2022 at the Rheumatology Clinic of Sivas Cumhuriyet University Faculty of Medicine Hospital. This observational case-control study included 35 patients with RA and 31 age- and sex-matched healthy controls. Serum levels of GRP78, eIF2α, ATF4, CHOP, caspase-3, and caspase-9 were measured using enzyme-linked immunosorbent assay. Disease activity was assessed using the Disease Activity Score-28 (DAS28). Statistical analyses included group comparisons, receiver operating characteristic curve analysis, and Spearman correlation analyses. A total of 67 participants (35 RA, 32 controls) were included. GRP-78, ATF4, eIF2α, caspase-3, and caspase-9 levels were significantly higher in RA patients (all p < 0.01), whereas CHOP levels were comparable between groups (p = 0.103). Caspase-3 demonstrated the highest discriminatory performance (AUC = 0.774, 95% CI: 0.656-0.891; p < 0.001). Caspase-3 and caspase-9 remained independently associated with RA in multivariable analysis. No significant correlations were observed between ER stress markers and DAS28 scores. Circulating ER stress-related apoptotic markers, particularly caspase-3 and caspase-9, were found to be associated with rheumatoid arthritis and may represent exploratory candidate biomarker signals reflecting the potential involvement of ER stress-apoptosis pathways in disease pathophysiology.

Keywords:  Apoptosis; Biomarkers; Caspase-3; Caspase-9; Endoplasmic reticulum stress; Rheumatoid arthritis; Surveys and questionnaires

DOI:  https://doi.org/10.1007/s00296-026-06236-8
Sci Rep. 2026 Jul 14.

Induction of paraptotic cell death in breast cancer cells by an iron chelator involved activation of UPR/MAPK pathway and inactivation of PI3K/AKT/mTOR.

Lei Yuan, Siwen Dong, Yong Shao, Changzheng Li.

Breast cancer is the most frequently diagnosed cancer in the world, but its treatment effect is limited, so new treatment strategies are needed. An iron chelator, 2,2'-di-pyridineketone hydrazone dithiocarbamate butyric acid ester (DpdtbA), exerts significant growth inhibition in breast cancer cell lines. Our data showed that DpdtbA treatment significantly promoted extensive cytoplasmic vacuolization derived from the endoplasmic reticulum, mitochondrial swelling, and Alix downregulation in MDA-MB-231 and SK-BR-3 cell lines. Furthermore, cytoplasmic vacuolation could be abolished by cycloheximide (CHX) and antioxidant N-acetylcysteine (NAC), indicating that vacuole formation required new protein synthesis and was ROS-dependent. These results support that DpdtbA is able to induce paraptosis, a programmed cell death pattern. The enhanced cytoplasmic Ca2+after DpdtbA treatment or deceased Ca2+ upon co-treatment with the Ca2+ chelator (BAPTA-AM) prompted that ROS production may partially correlate with the Ca2+-mediated decrease in mitochondrial membrane potential. In addition, DpdtbA triggered ER stress and accumulation of unfolded proteins, leading to the activation of p-PERK/p-EIF2α and p-IRE1/ATF4/chop pathway, inactivation of ATF6 (activating transcription factor 6) that may contribute to the anti-proliferative effect. Furthermore, our data showed that DpdtbA treatment not only led to excessive activation of MAPKs (mitogen activated protein kinases) signaling, but also resulted in inactivation of the PI3K/AKT/mTOR pathway, both of which were involved in the regulation of paraptosis. The results demonstrated that paraptotic cell death induced by an iron chelator in breast cancer cells was partially involved in Ca2+-mediated ROS production, UPR(unfolded protein response)/MAPKs activation, and PI3K/AKT/mTOR inactivation.

DOI: https://doi.org/10.1038/s41598-026-62456-9
Biochimie. 2026 Jul 17. pii: S0300-9084(26)00167-7. [Epub ahead of print]

ER quality control: how cells detoxify their own membrane from lipid stress.

Helin Elhan, Abdou Rachid Thiam.

  The endoplasmic reticulum (ER) is the principal site of glycerolipid synthesis in eukaryotic cells. The continuous production of lipid intermediates, including phosphatidic acid (PA), diacylglycerol (DAG), and triacylglycerol (TAG), destabilizes the ER membrane when they accumulate. To maintain bilayer integrity, cells deploy two sequential strategies: enzymatic conversion of these intermediates into membrane-compatible phospholipids, and their physical sequestration into lipid droplets (LDs), ER-derived organelles whose biogenesis is actively regulated by the seipin complex. LD growth is further sustained by the relocalization of TAG-synthesizing enzymes to the LD surface and by bridge-like lipid transfer proteins at ER-LD contact sites. When these mechanisms are overwhelmed, the accumulation of non-bilayer lipids drives ER stress and lipotoxicity, thereby contributing to the development of metabolic diseases. Here, we review the molecular logic of ER lipid quality control, from intermediate-driven membrane stress to the regulated responses that neutralize it.

Keywords:  Diacylglycerol; Kennedy pathway; endoplasmic reticulum; ferroptosis; lipid droplets; lipid quality control; lipotoxicity

DOI:  https://doi.org/10.1016/j.biochi.2026.07.007
bioRxiv. 2026 Jul 10. pii: 2026.07.09.737329. [Epub ahead of print]

Cell-type-specific ATF6α programs regulate epithelial mitochondrial homeostasis and pericyte remodeling during physiological and exposure-accelerated lung aging.

Xuejian Huang, Jonathan E Bard, Bat-Ider Tumenbayar, Kokilavani Vedagiri, Caryn E Nelson, Harshavardhan Kenche, Celia E Reynolds, Adriana S Leme, Stephen J Moore, Noa A Perry, Steven D Shapiro, Yaron Perry, Yongho Bae, Anna Blumental-Perry.

Proteostasis declines with lung aging, while the role of the Unfolded Protein Response (UPR) in lung aging and age-associated pulmonary diseases remains understudied. We investigated how deficiency in the UPR sensor ATF6α affects physiological and smoke exposure-accelerated lung aging. ATF6α -deficient mice exhibited accelerated alveolar simplification, a sign of lung parenchymal aging, which was exacerbated by smoking. Nevertheless, small airway vascular fibrotic remodeling, a prominent smoking induced pathology, was not evident in smoke-exposed ATF6α -deficient mice. Mechanistically, these divergent phenotypes arose from cell-type-specific ATF6α programs. In alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of the lung parenchyma, ATF6α maintained mitochondrial bioenergetics and sustained efficient re-differentiation into alveolar epithelial type 1 cells (AEC1s). In lung pericytes, ATF6α promoted extravasation, re-differentiation into myofibroblast-like cells, and production of collagens 1 and 3. These findings identify ATF6α as a cell-type-specific regulator of differentiation programs during lung aging and highlight the need to study ATF6α under defined physiological and pathological contexts before therapeutically targeting this pathway.

DOI: https://doi.org/10.64898/2026.07.09.737329
EMBO J. 2026 Jul 16.

Developmental priming of adult proteostasis and longevity by NuA4 complex activity in early life.

Yihan Wang, Xiong Xiong, Runshuai Zhang, Long Xiao, Xinyu Ruan, Tianyi Ni, Zicheng Liu, Jie Chen, Shenlu Qin, Zhuo Du, Yanxiao Zhang, Lianfeng Wu.

Proteostasis collapse, a hallmark of aging and neurodegeneration like Alzheimer's disease (AD), causes irreversible damage in late life. Whether late-life proteostasis capacity is developmentally programmed remains unclear, as mechanistic studies requiring lifelong tracking and molecular manipulation are challenging or impossible in long-lived species. Using C. elegans as a lifelong, genetically tractable AD model, we uncover a critical early-life window during which reducing TIP60/NuA4 acetyltransferase complex activity enduringly enhances proteostasis and extends lifespan. Mechanistically, NuA4 reduction depletes H4K16ac, triggering a compensatory, early-life-biased, XBP-1-mediated unfolded protein response (UPRER). This UPRER activation remodels endoplasmic reticulum (ER) morphology and reprograms lipid metabolism, driving selective oleic acid (OA) accumulation. Crucially, this developmentally-installed OA reservoir confers lasting resilience against proteotoxic stress, an effect mimicked by OA supplementation. Together, these findings establish a chromatin-ER-lipid axis that developmentally primes adult proteostasis and suggest early-life interventions as a strategy to promote healthy aging and resilience to proteotoxic stress.

DOI: https://doi.org/10.1038/s44318-026-00851-8
Nat Commun. 2026 Jul 16.

The unfolded protein sensor IRE1 is essential for homeostatic dendritic cell maturation.

Victor Bosteels, Sandra Maréchal, Eva Cloots, Farzaneh Fayazpour, Clint De Nolf, Laurien Van Heddegem, Simon J Tavernier, Sofie Rennen, Seraja Amstelveen, Liesbet Martens, Evelien Van De Velde, Delphine De Sutter, Annick Verhee, Kim Deswarte, Wouter Saelens, Louis Boon, Julie Van Duyse, Gert Van Isterdael, Isabelle Guillas, Yvan Saeys, Bruno De Geest, Sven Eyckerman, Pieter Mestdagh, Bart N Lambrecht, Wilfried Le Goff, Sophie Janssens.

Conventional type I dendritic cells (cDC1s) undergo homeostatic maturation upon apoptotic cell engulfment, hallmarked by the activation of the transcription factor LXRβ, which mediates cholesterol efflux and dampens interferon-stimulated gene expression. Here, we identify the unfolded protein response sensor IRE1 as an essential regulator of this process. Loss of IRE1 impairs cDC1, but not cDC2, homeostatic maturation and survival. IRE1 activation depends on apoptotic cell uptake and cholesterol influx, explaining its high basal activity in cDC1s. Rather than inducing a canonical unfolded protein response, IRE1 triggers a steady-state regulated IRE1-dependent decay program that degrades miR-92a-1, a microRNA targeting the cholesterol-efflux transporter Abcg1. Consequently, IRE1-deficient cDC1s show impaired cholesterol efflux and increased death, which can be rescued by blocking miRNA synthesis or treatment with reconstituted high-density lipoprotein. These findings establish IRE1 as a cholesterol sensor in cDC1s and reveal a parallel pathway to LXR that coordinates cholesterol homeostasis during DC maturation.

DOI: https://doi.org/10.1038/s41467-026-75716-z