bims-unfpre 2026-10-18 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–10–18
twelve papers selected by
Susan Logue, University of Manitoba

Subcellular spatiotemporal proteomics delineates distinct phases of ER stress proteostatic response.
Understanding the unfolded protein response in glioblastoma.
ER stress selects for Candida auris survivors with acquired fluconazole resistance and caspofungin tolerance.
Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.
Endoplasmic reticulum stress, redox signaling, and neutrophil effector functions in chronic lung diseases: Evidence and research priorities.
P4HA1 sustains endocrine resistance in luminal breast cancer via regulation of cellular stress.
Bi-allelic variants in the secretory pathway gene SEC16A are associated with a neurodevelopmental disorder.
A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex.
CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma.
HnRNPK suppresses macrophage-driven inflammation in autoimmune myocarditis by restraining NCF1-dependent oxidized phospholipid signaling and ferroptosis-related changes.
Palmitate-activated IRE1-XBP1 signaling limits DNA damage and is associated with H2A.X-linked DNA damage response transcripts in triple-negative breast cancer cells.
Activating transcription factor 6 is involved in the beneficial effects of growth hormone-releasing hormone antagonists in the corneal endothelium.

bioRxiv. 2026 Sep 28. pii: 2026.09.25.754245. [Epub ahead of print]

Subcellular spatiotemporal proteomics delineates distinct phases of ER stress proteostatic response.

Lorena Alamillo, Thalia Paiz, Alexander Black, Matthew C Juber, Ethan M Arends, Jacob G Cox, Dominic C M Ng, Timothy A McKinsey, Maggie P Y Lam, Edward Lau.

Endoplasmic reticulum (ER) stress is associated with many human diseases, but current understanding of how ER stress responses reshape the stressed proteome over time is still emerging. Specifically, how organellar protein quality control and clearance pathways coordinate to maintain proteostasis in early and prolonged ER stress is unclear. Here we describe a spatiotemporal proteomic strategy termed simultaneous proteome localization and turnover analysis with time resolution (SPLAT-TR) to interrogate the synthesis, degradation, and localization changes of over 4,000 proteins in early (1-4 hours) and prolonged (16-24 hours) ER stress. As ER stress progresses, each time point is distinguished by distinct protein translocation and clearance regulations, coupled to differential organellar proteostasis and usage of protein degradation pathways. Mitochondria show a bimodal response, with a shift from early activation of respiratory protein towards protein quality control pathways in prolonged stress, coinciding with energetics decline. In the Golgi, the increased clearance of collagen proteins is paradoxically coupled to an increased synthesis of secretory pathway components, suggesting removal by secretion. In the ER, the proteome remodels under prolonged stress via increased synthesis of UFMylation and ER-phagy-related proteins coupled to the selective degradation of ER membrane and microdomain proteins. Inhibition of UFMylation alters ER-phagy receptor usage and synergistically induces stress-induced cell death. These results present a systematic delineation of cell compartment proteostasis under unfolded protein response and highlight the utility of SPLAT-TR to investigate time-dependent cellular events.

DOI: https://doi.org/10.64898/2026.09.25.754245
J Cell Sci. 2026 Oct 01. pii: jcs264879. [Epub ahead of print]139(19):

Understanding the unfolded protein response in glioblastoma.

Kaixiang Ni, Chenchen Shi, Jiantong Jiao, Jun Sun, Yan Chen, Yi Liu.

  Glioblastoma is the most aggressive and lethal malignancy of the central nervous system and exhibits a complex interplay with endoplasmic reticulum (ER) stress (ERS). The multifunctional ER is the primary site of the unfolded protein response (UPR), which is activated under conditions of ERS to enhance protein-folding capacity and promote cell survival. However, persistent ERS can trigger apoptosis. Despite extensive research over the past decades, the mechanistic insights into the impact of ERS and the UPR on glioblastoma pathogenesis and progression remain unclear. The UPR operates through three canonical signaling pathways: inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK, also known as EIF2AK3) and activating transcription factor 6 (ATF6). These pathways regulate glioblastoma development through both independent and synergistic mechanisms. In this Review, we discuss the current state of research on the role of the UPR in glioblastoma and delineate the distinct mechanisms of each signaling pathway. Furthermore, we evaluate the challenges associated with UPR-targeting therapeutic agents and propose possible treatment strategies to leverage the regulatory mechanisms of the different UPR pathways to overcome these limitations.

Keywords:  Apoptosis induction; Drug resistance; Glioblastoma; Targeted therapy; Unfolded protein response

DOI:  https://doi.org/10.1242/jcs.264879
Front Microbiol. 2026 ;17 1845986

ER stress selects for Candida auris survivors with acquired fluconazole resistance and caspofungin tolerance.

Feng Yang, Liuliu Sun, Hao Li, Ting Fang, Qinli Guo, Nan Chen, Yuanying Jiang.

  Exposure to endoplasmic reticulum (ER) stress can drive the emergence of antifungal resistance in pathogenic fungi, but the underlying mechanisms remain poorly understood. Here, we show that treatment of Candida auris B12037 (clade 3) with the ER stressor tunicamycin selects for survivors with acquired resistance to fluconazole and, in a subset, tolerance to caspofungin. Pharmacological inhibition revealed that caspofungin tolerance, but not fluconazole resistance, requires the Hsp90-calcineurin axis. RNA-seq analysis of the parental strain exposed to tunicamycin uncovered a coordinated stress response characterized by up-regulation of cell wall biosynthesis, transmembrane transport, and autophagy, alongside global repression of translation and energy metabolism. In the resistant survivors, fluconazole resistance correlated with up-regulation of the efflux pump MDR1, with isolate #10 additionally exhibiting ERG11 overexpression. Caspofungin tolerance in isolate #10 was associated with up-regulation of multiple chitin synthase genes (CHS1, CHS3, CHS5), suggesting chitin-mediated cell wall remodeling. Isolate #19 displayed a distinct pattern, indicating alternative mechanisms of caspofungin tolerance. These findings reveal that ER stress selects for C. auris survivors with divergent antifungal resistance profiles through distinct molecular pathways, highlighting the potential for stress-induced evolution of multidrug resistance in this critical pathogen.

Keywords:  Candida auris; ER stress; Hsp90-calcineurin axis; antifungal resistance; antifungal tolerance

DOI:  https://doi.org/10.3389/fmicb.2026.1845986
Cells. 2026 Sep 23. pii: 1733. [Epub ahead of print]15(19):

Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.

Sara Anjum Niinuma, Ashleigh Suzu-Nishio Takemoto, William Junior Khalil, Alexandra E Butler, Abu Saleh Md Moin.

  Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca2+ release with mitochondrial Ca2+ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER-mitochondria crosstalk sustains β-cell health through Ca2+ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP3) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca2+ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.

Keywords:  MAMs; mitochondrial-associated membranes; β-cell dysfunction; β-cell stress

DOI:  https://doi.org/10.3390/cells15191733
Free Radic Biol Med. 2026 Oct 10. pii: S0891-5849(26)01195-0. [Epub ahead of print]257 315-330

Endoplasmic reticulum stress, redox signaling, and neutrophil effector functions in chronic lung diseases: Evidence and research priorities.

Su Bin Park, Tae Han Yook, Mohammad Mamun Ur Rashid, Kangwook Lee, Jong Uk Kim, Dae Yong Kim, Mi Hye Kim, Ji Yong Jang, Gabsik Yang.

  Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling intersect with inflammatory and redox pathways. Experiments in primary neutrophils link selected UPR pathways to mitochondrial reactive oxygen species, neutrophil extracellular trap (NET) formation, antimicrobial activity, and immune regulation under defined conditions. This review organizes these findings by cell type, experimental model, and the relationship tested, distinguishing them from cell-line experiments, other-cell mechanisms, clinical associations, and database connections. We examine calcium signaling, compartmentalized oxidant production, antioxidant defenses, and redox-dependent UPR sensor modifications. Several molecular mechanisms of sensor modification derive from non-neutrophil systems and require separate validation in neutrophils. Their relevance is assessed across chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis, with cystic fibrosis (CF) blood-neutrophil transcript measurements distinguished from functional pathway evidence. To our knowledge, no study has established direct causality between neutrophil-intrinsic UPR signaling and NET formation in primary neutrophils obtained from human chronic lung disease tissue or pulmonary neutrophilic patient cohorts. We identify dose-, time-, and branch-resolved experiments needed to evaluate individual neutrophil functions without assigning their direction to acute or prolonged stress. Pharmacological UPR modulation is considered separately from delivery platforms evaluated with non-UPR cargoes. This evidence-based assessment defines the cellular boundaries of current knowledge and prioritizes experiments needed to establish disease relevance and preserve antimicrobial defense.

Keywords:  Endoplasmic reticulum stress; Lung diseases; Neutrophil effector functions; Redox signaling; Unfolded protein response

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.014
bioRxiv. 2026 Oct 01. pii: 2026.09.30.755755. [Epub ahead of print]

P4HA1 sustains endocrine resistance in luminal breast cancer via regulation of cellular stress.

Dalton Hironaka, Baorui Kang, Dongsung Kim, Haichang Li, Rachel Schiff, Ren Xu, Gaofeng Xiong.

The hormone receptor-positive luminal subtype accounts for approximately 70% of all diagnosed breast cancer cases, with endocrine regimens serving as the first-line therapy. However, 30% to 50% of luminal breast cancer patients acquire therapeutic resistance with five to ten years of treatment. Understanding the mechanisms of endocrine resistance and identifying new therapeutic targets remain urgent priorities. Here, we demonstrate that expression of the alpha subunit of prolyl 4-hydroxylase (P4HA1), a key collagen-modifying enzyme, is significantly upregulated in endocrine therapy-resistant luminal breast cancer cells compared to parental endocrine therapy-sensitive cells. Clinically, elevated P4HA1 expression correlates with shortened relapse-free survival in patients with luminal breast cancer. Genetically knocking down P4HA1 or pharmacologically inhibiting its activity successfully restores the sensitivity of endocrine-resistant luminal breast cancer cells to hormone therapy. Mechanistically, we reveal that combining P4HA1 inactivation with endocrine treatment dramatically enhances endoplasmic reticulum (ER) stress-related gene expression. Consistently, treating resistant cells with an exogenous ER stress inducer similarly enhances sensitivity to hormone therapy. Furthermore, we demonstrate that ER stress induced by P4HA1 inactivation is molecularly mediated by an accumulation of reactive oxygen species (ROS). Together, these findings uncover a novel, non-canonical role for P4HA1 as a critical mediator linking endocrine resistance to cellular stress adaptations, positioning P4HA1 as a promising therapeutic vulnerability in endocrine-resistant breast cancer. P4HA1 serves as a necessary role in maintenance resistant state, making it a viable target for combination therapies to overcome endocrine resistance.

DOI: https://doi.org/10.64898/2026.09.30.755755
J Clin Invest. 2026 Oct 13. pii: e199882. [Epub ahead of print]

Bi-allelic variants in the secretory pathway gene SEC16A are associated with a neurodevelopmental disorder.

Mengqi Ma, Xiaowei Lei, Juan Li, Yiming Zheng, Yu Yuan, Yohei Nitta, Xiao Mao, Zhenming Guo, Shenzhao Lu, Mingxi Deng, Xueyang Pan, Oguz Kanca, Shiyi Liu, Hua Wang, Bo Xiao, Rachel Schot, Serwet Demirdas, Yolande van Bever, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Shan Bian, Hugo J Bellen, Lili Long.

  SEC16A encodes a scaffold protein that organizes the endoplasmic reticulum (ER) exit sites, specialized ER subdomains that mediate export of newly synthesized proteins and regulate early secretory pathway steps. The role of SEC16A in human nervous system diseases has not been established yet. Here, we report six individuals with bi-allelic SEC16A variants who presented with early-onset neurological symptoms, including cognitive impairment, motor delays, and seizures. Using Drosophila, we show the Sec16 ortholog is essential for normal development and that its loss causes early lethality. Neuron-specific knockdown of Sec16 causes neurological phenotypes including locomotor defects, seizure-like bang sensitivity, and impaired synaptic transmission, which can be associated with the clinical features observed in affected individuals. Neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) carrying SEC16A variants display reduced SEC16A protein, impaired neurite outgrowth and increased excitability, which are rescued in isogenic control neurons when the variants are corrected, consistent with a loss-of-function mechanism. Increased ER stress was observed in both patient iPSC-derived neurons and fly models. In summary, our findings indicate a conserved requirement for SEC16A in neurodevelopment and neuronal function and implicate ER stress as a key cellular phenotype underlying the SEC16A-associated neurodevelopmental disorder.

Keywords:  Genetics; Neurodevelopment; Neuroscience; Protein traffic

DOI:  https://doi.org/10.1172/JCI199882
Cell Rep. 2026 Oct 13. pii: S2211-1247(26)01215-5. [Epub ahead of print]45(10): 118136

A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex.

Ivan Vlassakev, Christina Savva, Liying Zhou, Danilo Ritz, Alexander Schmidt, Cholsoon Jang, Amir Ata Saei, Paul Petrus.

  Daily light-dark cycles impose environmental fluctuations that require coordinated regulation of physiology. This coordination is mediated by the circadian clock, which operates as a network of tissue oscillators; however, the signals that convey circadian information between organs remain incompletely defined. We identify nicotinic acid riboside (NaR) as a circulating metabolite whose rhythmicity depends on the liver clock. In adipocytes and neuronal cells, NaR engages the unfolded protein response (UPR). Proteome-wide stability profiling implicates the prefoldin complex as a target of NaR, linking NaR exposure to altered proteostasis. In adipocytes, NaR-induced UPR signaling converges on the transcription factor CCAAT/enhancer-binding protein alpha (CEBPA). Sustained NaR exposure suppresses adipocyte lipid deposition, whereas temporally restricted NaR stimulation enhances adipogenesis. Together, these findings identify NaR as a liver clock-controlled circulating metabolite that couples systemic circadian metabolism to proteostasis and tissue remodeling, revealing a mechanism by which temporal metabolic signals shape tissue-specific physiological outcomes.

Keywords:  CP: metabolism; CP: molecular biology; adipocyte; circadian rhythms; metabolism; organ communication; systems biology; unfolded protein response

DOI:  https://doi.org/10.1016/j.celrep.2026.118136
Nat Commun. 2026 Sep 11. pii: 10714. [Epub ahead of print]17(1):

CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma.

Liliana Mirabal-Ortega, Sandra Majo, Lucie J Taunay, Magalie Larcher, Dave Yong Xiang Ng, Sara Chabi, Marion Le Grand, Kevin Muller, Jacob Torrejon, Laure Lagaye, Sofia Gaid, Coline Kerbaj, Moustapha Ka, Cristèle Gilbert, Véronique Marsaud, Bertrand Duvillié, Marine Blanchard, Boris Julien, Sophie Leboucher, Florent Dingli, Damarys Loew, Franck Griscelli, Annelise Bennaceur-Griscelli, Franck Bourdeaut, François Doz, Olivier Ayrault, Florence M Cavalli, Michael D Taylor, Alain Eychène, Rachid Benhida, Eric Chevet, Eddy Pasquier, Sabine Druillennec, Celio Pouponnot.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The MYC‑amplified group 3 (G3) MB represents a high‑risk disease lacking effective therapies. A genetic screen identified the endoplasmic reticulum chaperone HSPA5 (BiP/GRP78) as a critical dependency in G3 MB. Its silencing induces apoptosis and suppresses tumor growth, with strong activation of the unfolded protein response (UPR). The UPR includes three branches, including the PERK-eIF2α axis, which transiently reduces global protein synthesis while enabling selective translation of stress‑responsive factors such as ATF4. We show that G3 MB requires sustained eIF2α activity for survival. Its inhibition triggers cell death through ATF4‑dependent and ‑independent transcriptional programs and translational reprogramming that deplete essential proteins and promote accumulation of detrimental factors. The eIF2α phosphatase PPP1R15B (CReP) maintains basal eIF2α activity and prevents apoptosis. These findings identify the eIF2α axis and its regulators as a crucial node and a targetable vulnerability in G3 MB.

DOI: https://doi.org/10.1038/s41467-026-77565-2
Redox Biol. 2026 Oct 08. pii: S2213-2317(26)00428-3. [Epub ahead of print]98 104429

HnRNPK suppresses macrophage-driven inflammation in autoimmune myocarditis by restraining NCF1-dependent oxidized phospholipid signaling and ferroptosis-related changes.

Han Li, Wenhu Liu, Jing Hu, Jingjie Xiong, Xuehua Wang, Jiaxi Lv, Ni Xiong, Yanling Huang, Qianyi Liu, Lihui Yin, Yan Wang, Ya Wang, Zhaohui Wang.

  NADPH oxidase-dependent ROS production, oxidized phospholipid (OxPL) signaling, and macrophage ferroptosis are emerging drivers of inflammatory cardiac injury, yet the upstream regulatory mechanisms governing these processes remain poorly understood. Here, we identify heterogeneous nuclear ribonucleoprotein K (HnRNPK), a multifunctional RNA-binding protein, as a post-transcriptional regulator of macrophage oxidative stress and ferroptosis-related changes in experimental autoimmune myocarditis (EAM). HnRNPK was significantly downregulated in EAM cardiac tissues and inflammatory macrophages, whereas AAV-HnRNPK administration attenuated myocardial inflammatory infiltration, fibrosis, and cardiac dysfunction and reduced macrophage pro-inflammatory activation. Mechanistically, HnRNPK regulated the balance between NR_104383 and coding Ncf1 transcripts, while NR_104383 knockdown and NCF1 add-back partially reversed its anti-inflammatory effects in BMDMs. NCF1 promoted ROS generation, lipid peroxidation, E06-reactive OxPL signals, mitochondria-associated ER membrane (MAM) remodeling, ER stress, and macrophage ferroptosis-related phenotypes. E06 treatment attenuated NCF1-associated MAM remodeling and partially restored GPX4 expression, whereas oxPAPC increased ER-mitochondria contacts and related molecular changes that were attenuated by E06. Together, these findings establish a functional HnRNPK/NR_104383/NCF1 axis linking alternative transcript regulation to NCF1-dependent redox injury, OxPL-associated MAM remodeling, and ferroptosis-related changes in inflammatory macrophages.

Keywords:  Alternative splicing; Autoimmune myocarditis; Ferroptosis; Mitochondria-associated ER membranes; NADPH oxidase; Oxidized phospholipids

DOI:  https://doi.org/10.1016/j.redox.2026.104429
bioRxiv. 2026 Sep 28. pii: 2026.09.25.754433. [Epub ahead of print]

Palmitate-activated IRE1-XBP1 signaling limits DNA damage and is associated with H2A.X-linked DNA damage response transcripts in triple-negative breast cancer cells.

Kevin Y Chen, Elaina Gouin, Ava Erickson, Yogit Goyal, Samantha Zaloudek, Sean Foster, Caleb Sandum, S Patrick Walton, Christina Chan.

Palmitate-associated lipotoxic stress activates the endoplasmic-reticulum stress sensor protein IRE1, but how IRE1 signaling influences genotoxic-stress responses in triple-negative breast cancer remains unclear. Here, we investigated IRE1 and XBP1 signaling in MDA-MB-231 cells exposed to palmitate and etoposide. Under combined lipotoxic and genotoxic stress, XBP1 depletion increased DNA-damage accumulation in IRE1 wild-type cells but not in IRE1-deficient cells, whereas IRE1 re-expression reduced DNA damage. Pharmacologic IRE1 RNase inhibition also increased etoposide-associated DNA damage, supporting a protective role for IRE1 RNase-dependent signaling. IRE1 status and XBP1 manipulation differentially affected H2A.X and γH2A.X abundance, indicating context-dependent regulation of chromatin-associated DNA-damage signaling. At the RNA level, H2A.X was enriched in IRE1 immunoprecipitates, and the H2A.X-linked DNA-damage-response transcripts HUWE1 and BRCA2 also associated with IRE1 under combined stress. These findings link palmitate-activated IRE1-XBP1 signaling to genome-protective responses during genotoxic stress and identify a network of IRE1-associated DNA-damage-response transcripts in triple-negative breast cancer cells. Direct IRE1-mediated cleavage of these transcripts remains to be established.

DOI: https://doi.org/10.64898/2026.09.25.754433
Front Ophthalmol (Lausanne). 2026 ;6 1946815

Activating transcription factor 6 is involved in the beneficial effects of growth hormone-releasing hormone antagonists in the corneal endothelium.

Md Matiur Rahman Sarker, Saikat Fakir, Madan Sigdel, Nektarios Barabutis.

  The corneal endothelium maintains eye transparency through fluid regulation, and its dysfunction has been associated with impaired vision. This study is focused on the possible involvement of activating transcription factor 6 (ATF6) in the beneficial effects of Growth Hormone - Releasing Hormone antagonists (GHRHAnt) in corneal cells. ATF6 is a UPR sensor involved in barrier function, previously shown to exert anti-inflammatory activities. The aim of this study is to evaluate involvement of ATF6 in the effects of GHRHAnt in the corneal endothelium. MTT assay was used to measure the cell viability of ATF6 modulator. We demonstrated the efficient ATF6 manipulation by AA147 and Ceapin-A7, which are specific ATF6 modulators. Western blot analysis was used to detect the protein expression levels. FITC-dextran assay and DCFDA were utilized to measure paracellular permeability and reactive oxygen species generation, respectively. AA147 enhanced Grp94 and BiP expression, both being downstream ATF6 targets, whereas Ceapin-A7 exerted the opposite effects. Then, we investigated the possible involvement of ATF6 in the protective activities of GHRHAnt in the corneal endothelium. ATF6 activation enhanced the protective effects of GHRHAnt by reducing paracellular permeability and ROS generation, while ATF6 inhibition exerted the opposite effects. Our study suggests that ATF6 mediates - at least in part - the beneficial effects of GHRHAnt in the cornea.

Keywords:  endothelium; growth hormone; inflammation; keratitis; unfolded protein response

DOI:  https://doi.org/10.3389/fopht.2026.1946815