bims-unfpre 2026-10-25 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–10–25
ten papers selected by
Susan Logue, University of Manitoba

A role for eIF5A in translational control of stress-inducible proteins in multiple myeloma cell lines.
Polycystin-2 functions as a calcium leak channel under endoplasmic reticulum stress to protect against myocardial ischemia.
Diet-induced diabetes driven by proinsulin misfolding reversed by β-cell rest.
Comprehensive assessment of unfolded protein response and its association with tumor progression in pan-cancer.
The endoplasmic reticulum autophagy receptor TEX264 drives epidermal differentiation and is dysregulated in Darier disease.
Endoplasmic reticulum stress in autoimmune skin diseases: immune activation, cutaneous cell damage, and therapeutic advances.
Paraptosis, a new type of cell death that can be applied to cancer treatment.
The conserved NUS-1/DHDDS-1 complex links N-glycosylation to lipid and lysosomal homeostasis in C. elegans.
Discovery of a Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) Inhibitor Suitable for Clinical Progression.
Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity.

Mol Oncol. 2026 Oct 21.

A role for eIF5A in translational control of stress-inducible proteins in multiple myeloma cell lines.

Demi Both, Ingrid A M Derks, Raphaël Vanleyssem, Marine Leclercq, Najla El Hachem, Pierre Close, Eric Eldering, Marco Vincent Haselager.

  Impaired protein folding in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR), which can induce apoptosis during prolonged ER stress. ER stress is therapeutically targeted in plasma cell malignancies, such as multiple myeloma (MM), but these treatments remain noncurative, and UPR signaling in B-cell malignancies is incompletely understood. A targeted CRISPR-Cas9 screen in RPMI-8226 cells exposed to thapsigargin identified known ER stress regulators (XBP1, IRE1, and calreticulin) and the translation factor eIF5A (eukaryotic translation initiation factor 5A), whose role in ER stress remains unclear. Competition assays showed that eIF5A depletion is detrimental under basal conditions but confers a proliferation advantage during thapsigargin treatment. Inducible EIF5A knockouts confirmed reduced sensitivity specifically to thapsigargin, loss of eIF5A had no or sensitizing effects on cell death induced by other ER stress drugs. Polysome profiling revealed that not general translation, but the translation of specific mRNA transcripts coding for UPR components and apoptotic proteins was affected by eIF5A depletion. Correspondingly, EIF5A KO cells showed reduced thapsigargin-induced UPR activation. In conclusion, these findings indicate that loss of eIF5A alters the stress response in MM cells.

Keywords:  ER stress; UPR; apoptosis; eIF5A; multiple myeloma; translation

DOI:  https://doi.org/10.1002/1878-0261.70328
Cell Rep. 2026 Oct 20. pii: S2211-1247(26)01245-3. [Epub ahead of print]45(11): 118166

Polycystin-2 functions as a calcium leak channel under endoplasmic reticulum stress to protect against myocardial ischemia.

Virdjinija Vuchkovska, Sanjeet Paluru, Ryne M Knutila, Djamilla Simoens, Karla M Márquez-Nogueras, Elisabeth DiNello, Quan Cao, Jonathan A Kirk, Ivana Y Kuo.

  Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) to enhance metabolism and restore homeostasis by increasing mitochondrial calcium at mitochondrial-endoplasmic reticulum contact sites (MERCs). Unresolved ER stress is deleterious and contributes to the severity of diseases such as myocardial infarction (MI). The identity of the MERC calcium source and its interplay with the UPR is unclear. We find that ER-localized polycystin-2 (PC2), a calcium channel, is upregulated in cardiomyocytes with MI. Cardiomyocyte PC2-knockout mice with MI exhibit worsened heart function and decreased PERK. ER stress induces a PC2-facilitated adaptive ER calcium leak and PC2 localization to MERCs. PC2 requires PERK phosphorylation for mitochondrial calcium transfer. PC2 mutations impair ER calcium leak, restored by full-length PC2 expression. Thus, PC2 functions in a PERK-dependent manner under ER stress to provide mitochondrial calcium, and its upregulation is cardioprotective in MI.

Keywords:  CP: cell biology; ER stress; MERCs; MI; PC2; PERK; calcium leak; cardiomyocytes

DOI:  https://doi.org/10.1016/j.celrep.2026.118166
Mol Metab. 2026 Oct 22. pii: S2212-8778(26)00145-6. [Epub ahead of print] 102461

Diet-induced diabetes driven by proinsulin misfolding reversed by β-cell rest.

Maroof Alam, Anoop Arunagiri, Leena Haataja, Sami B Onton, Chanté Liu, Mauricio Torres, Emma Mastroianni, Joshua Monickaraj, Hassan Draz, Leslie S Satin, Peter Arvan.

  Diet modification can be beneficial in the treatment of type-2 diabetes; but different dietary management approaches can have different impact on pancreatic islet β-cells. Congenic male mice carrying one Ins2-R(B22)E allele (encoding a proinsulin that is predisposed to misfolding, plus three alleles encoding WT proinsulin) develop diabetes prompted by high fat diet-induced weight gain, with exacerbation of β-cell ER stress. Here we sought to understand how β-cell rest could bring about reversal of diabetes. For this, we transitioned two groups of diabetic mice for 5-weeks of a lower caloric-density diet (normal chow ad lib) or alternatively, the same high fat diet alternating with fasting every other day. Both approaches yielded sets of animals that consumed the same total calories; both blocked further body weight gain leading to the same final body weight; both maintained the same energy expenditure; and both exhibited the same whole-body insulin sensitivity. However, diabetes was selectively reversed in animals fed high fat diet alternating with fasting, accompanied by significantly increased islet insulin content, and increased circulating insulin. Blood glucose and serum insulin levels oscillate in animals fed every other day; our data suggest β-cell rest on the fasting day. Mechanisms associated with recovery included decreased islet phospho-eIF2α, accompanied by increased proinsulin synthesis without a corresponding increase of the ER chaperone BiP. We conclude that one of the key features leading to the phenotype of enhanced β-cell maturity involves enhanced insulin biosynthesis without a concomitant increase in β-cell ER stress.

Keywords:  Alternate-day feeding; ER stress; Endoplasmic reticulum; proinsulin; β-cell maturity

DOI:  https://doi.org/10.1016/j.molmet.2026.102461
IMetaOmics. 2026 Mar;3(1): e70084

Comprehensive assessment of unfolded protein response and its association with tumor progression in pan-cancer.

Xinyu Yang, Faming Zhao, Jing Yang, Xinran Xia, Liwei Chen, Peng Zeng, Liang Chen, Yanxia Hu, Xia Sheng.

  Disruption of proteostasis in the endoplasmic reticulum leads to the activation of the unfolded protein response (UPR). UPR activation is common in malignant cells and is often considered a contributor to cancer progression. However, the accurate evaluation of UPR status in pan-cancer is still lacking. Furthermore, the UPR-related key characteristics in cancer progression remain to be explored. To fill in these gaps, we first proposed a UPR signature, according to which a UPR score was assigned to each tumor/tumor cell by gene set variation analysis. Based on this, we depicted the UPR landscape across 33 kinds of tumors and 28 kinds of normal tissues, which revealed significant inter- and intra-tumoral heterogeneity in UPR activity across different cancers. Next, by integrating bulk and single-cell transcriptomic data, we unveiled robust correlations of UPR activation with critical genomic and immune features amongst different cancers. In addition, by employing three machine learning algorithms, we identified and validated a promising biomarker derived from the perspective of UPR for breast cancer prognosis. In summary, our study offers an effective approach for evaluating UPR activity in human cancer and underscores the clinical significance of UPR activity in cancer progression.

Keywords:  endoplasmic reticulum stress; machine learning; pan‐cancer; single‐cell transcriptomics; unfolded protein response

DOI:  https://doi.org/10.1002/imo2.70084
JCI Insight. 2026 Oct 22. pii: e196831. [Epub ahead of print]

The endoplasmic reticulum autophagy receptor TEX264 drives epidermal differentiation and is dysregulated in Darier disease.

Christopher J Johnson, Afua Tiwaa, Arti Parihar, Edwin Antonio, Brooke D Lorenz, Reeteka Kudallur, Aaron Ramonett, Anthony Coon, Mrinal K Sarkar, Johann Gudjonsson, Cory L Simpson.

  Differentiating keratinocytes break down their organelles and nuclei to become the compacted cornified layers of the epidermal barrier in a poorly understood catabolic process. Live confocal imaging of stratified human organotypic epidermis revealed endoplasmic reticulum (ER) fragmentation and lysosomal engulfment in the cornifying layers, where we found up-regulation of TEX264, a receptor that mediates selective autophagy of the ER (reticulophagy). TEX264 expression was increased by ER stress, which caused precocious cornification of organotypic epidermis. In undifferentiated keratinocytes, ectopic TEX264 was sufficient to induce ER fragments, while in highly differentiated keratinocytes, it accelerated ER elimination and nuclear shrinkage; these effects were abolished by mutating the LC3 interacting region required for its autophagic function. Knockout of TEX264 or inhibiting its activation disrupted the maturation of organotypic cultures, pointing to a critical role for reticulophagy in cornification. Finally, in patient biopsies and an organotypic model of Darier disease, a genetic cornification disorder linked to ER dysfunction, we found increased TEX264 in areas of premature cornification (dyskeratosis). Our results identified TEX264 as a key driver of late-stage epidermal differentiation and led us to propose a model of cornification in which keratinocytes activate selective autophagy receptors to orchestrate orderly organelle elimination during cutaneous barrier formation.

Keywords:  Autophagy; Cell biology; Dermatology; Genetic diseases; Skin

DOI:  https://doi.org/10.1172/jci.insight.196831
Front Immunol. 2026 ;17 1980040

Endoplasmic reticulum stress in autoimmune skin diseases: immune activation, cutaneous cell damage, and therapeutic advances.

Jiaxi Qiao, Jia Chen, Jinbo Chen, Liuqing Chen.

  Endoplasmic reticulum stress (ERS) arises when the protein-folding load, or perturbations in calcium and redox homeostasis, outpace the adaptive capacity of the endoplasmic reticulum (ER). The unfolded protein response (UPR) initially reduces secretory load and restores proteostasis. Persistent stress can redirect the same pathways toward inflammatory signaling, altered antigen processing, and potentially immunogenic cell death. We term this context-dependent transition ERS-immune tolerance breaking, and propose it as a unifying framework for understanding how unresolved ERS may contribute to loss of cutaneous immune homeostasis. It is especially relevant in skin, where keratinocytes and melanocytes encounter ultraviolet radiation and oxidative injury while infiltrating immune cells face large biosynthetic demands. Evidence from vitiligo, pemphigus vulgaris, psoriasis, lupus erythematosus, and systemic sclerosis links dysregulated IRE1α, PERK, and ATF6 signaling to target-cell damage and immune amplification. In this review, we evaluate this evidence with particular attention to disease-specific mechanisms and the strength of causal inference supporting a pathogenic role for ERS. The case for a pathogenic role is strongest when ERS has been manipulated in defined cell types or experimental models; associations based only on UPR markers in lesions remain harder to interpret. Therapeutic studies also caution against treating the UPR as a uniformly harmful pathway. Intervention will probably need to preserve adaptive proteostasis while limiting the pathogenic output that predominates in a particular cell population and disease phase.

Keywords:  ERS–immune tolerance breaking; autoimmune skin diseases; cutaneous immunology; endoplasmic reticulum stress; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2026.1980040
Front Oncol. 2026 ;16 1959542

Paraptosis, a new type of cell death that can be applied to cancer treatment.

Xudong Wang, Jiaxing Ma, Bowen Tan, Yang Wang, Zhengwan Wang, Chunlan Hou, Qingjuan Chen, Xiang Jin.

  Paraptosis is a form of non-apoptotic cell death characterized by cytoplasmic vacuolization and swelling of the mitochondria and endoplasmic reticulum (ER). Recent studies have demonstrated that inducing paraptosis in cancer cells can circumvent apoptosis resistance and synergize with other forms of cell death and tumor immunity, providing a novel strategy for anti-tumor therapy. The underlying mechanism of paraptosis involves ER stress triggered by inducers, leading to the swelling of the ER and mitochondria. This subsequently alters the cytoskeleton and disrupts molecular processes, such as calcium (Ca2+) homeostasis, ultimately causing cytoplasmic vacuolization and cell death. Unlike other forms of programmed cell death, paraptosis is caspase-independent and is marked by mitochondrial and ER swelling, along with extensive cytoplasmic vacuolization, without nuclear pyknosis or cell membrane rupture. Various natural compounds, chemical agents, and nanomedicines have been shown to induce paraptosis, which also holds potential in immunotherapy by promoting immunogenic cell death (ICD) and systemic anti-tumor responses. Thus, in cases where cancer cells evade and develop resistance to conventional pro-apoptotic therapies, paraptosis induction offers an alternative therapeutic approach. A comprehensive understanding of the molecular mechanisms underlying paraptosis and its targeted induction may facilitate the development of novel cancer treatments. This paper explores the impact of paraptosis on cancer cells, the mechanisms by which different drugs induce paraptosis, and the potential applications of paraptosis in cancer therapy.

Keywords:  cancer therapy; cell death; endoplasmic reticulum; molecular mechanisms; paraptosis

DOI:  https://doi.org/10.3389/fonc.2026.1959542
Cell Rep. 2026 Oct 19. pii: S2211-1247(26)01257-X. [Epub ahead of print]45(11): 118178

The conserved NUS-1/DHDDS-1 complex links N-glycosylation to lipid and lysosomal homeostasis in C. elegans.

Meixi Gong, Wentao Zhao, Yilin Du, Lingfan Zhu, Yile Zhai, Yuxiao Xie, Chen Liu, Wenfei Li, Pei Zhao, Zhe Zhang.

  N-glycosylation is essential for proteome integrity, yet the systemic roles of the cis-prenyltransferase (cis-PT) complex remain poorly defined. Using Caenorhabditis elegans, we demonstrate that this complex is a dual regulator of global lipid and lysosomal homeostasis. Mechanistically, NUS-1 physically associates with the core oligosaccharyltransferase (OST) complex to coordinate N-glycan transfer. Loss of NUS-1/DHDDS-1 triggers endoplasmic reticulum stress, lysosomal collapse, and systemic lipopenia. This lipid defect arises from impaired N-glycosylation of the SREBP cleavage-activating protein (SCAP). cis-PT deficiency causes unglycosylated SCAP to undergo massive degradation and absolute physical entrapment within the ER, preventing SREBP nuclear translocation and downstream lipid synthesis. Furthermore, pathogenic mutations cause dysfunction through distinct molecular mechanisms: pocket integrity disruption or catalytic impairment. These findings uncover an essential crosstalk between protein glycosylation and global lipid metabolism, providing a mechanistic framework for understanding the systemic pathophysiology of congenital disorders of glycosylation (CDG).

Keywords:  CP: metabolism; CP: molecular biology; Caenorhabditis elegans; ER stress; N-glycosylation; NUS-1/DHDDS-1; SREBP; cis-prenyltransferase complex; lipid homeostasis; lysosomal homeostasis

DOI:  https://doi.org/10.1016/j.celrep.2026.118178
J Med Chem. 2026 Oct 22. 69(20): 24619-24644

Discovery of a Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) Inhibitor Suitable for Clinical Progression.

Paul A Glossop, Samuel Brookes, Neil Flanagan, Melanie S Glossop, Krishna K Kolluri, Charlotte A L Lane, Clara Stead, Susanne Wright, Richard P Butt, Nadine Clemo, Emmanuel H Demont.

  Protein kinase R-like endoplasmic reticulum kinase (PERK) is a key sensor in the integrated stress response (ISR) and the unfolded protein response (UPR), playing a critical role in tumor cell survival under stress conditions. Based on literature data, we identified the novel PERK inhibitor 17, of moderate potency but promising kinase selectivity and in vivo pharmacokinetics. A lead optimisation campaign focussing on careful control of lipophilicity (log D) and lipophilic ligand efficiency (LLE) led to the identification of 49 (APL-11056), a potent and selective PERK inhibitor. High permeability contributes to its excellent in vivo pharmacokinetics and can be linked to the presence of a fluorine alpha to the core benzamide, which limits recognition by efflux transporters.

Keywords:  PERK; clinical candidate; fluorine; kinase; lipophilic ligand efficiency; orthosteric inhibitor

DOI:  https://doi.org/10.1021/acs.jmedchem.6c02120
Front Immunol. 2026 ;17 1940201

Chronic XBP1s-mediated activation of the unfolded protein response impairs CD8+ T cell anti-tumor immunity.

Keith Alan Nair, Jessica Lee, Olivia Zaleski, Luciano Mazzoccoli, Brian Deng, Chih-Chi Andrew Hu, Stanley Ching-Cheng Huang, Andreas Wieland, Hazem E Ghoneim, Haitao Wen, Xiaopei Huang, Bei Liu.

  CD8+ T cells play a crucial role in anti-tumor immunity; however, their functionality is compromised by exhaustion driven by chronic antigen exposure, poor tumor microenvironment, and metabolic dysfunction. Activated CD8+ T cells undergo extensive proteomic remodeling, which includes the induction of the IRE1-XBP1 signaling axis of the unfolded protein response. However, the functional consequences of sustained IRE1-XBP1 activation in exhausted CD8+ T cells remain elusive. Using a model of constitutive XBP1 activation in CD8+ T cells, we demonstrate that sustained XBP1s signaling leads to reduced homeostatic CD8+ T cell populations, impaired migratory capacity, and dampened anti-tumor immunity. Notably, pharmacological inhibition of the IRE1-XBP1 axis significantly reduces tumor burden through a dual mechanism that targets both tumor cells and the immune compartment. Our findings reveal a previously unappreciated role for XBP1s in regulating CD8+ T cell biology and highlight the IRE1-XBP1 axis as a therapeutic target in solid tumors.

Keywords:  CD8+ T cells; T cell exhaustion; XBP1s; anti-tumor immunity; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2026.1940201