bims-unfpre 2026-02-22 papers

Issue of 2026–02–22
six papers selected by
Susan Logue, University of Manitoba

Cell Mol Biol Lett. 2026 Feb 14.

BIP orchestrates bidirectional ER protein trafficking via co-chaperone complexes.

Suma Biadsy, Ayelet Gilad, Laila Abu Madegam, Aeid Igbaria.

Keywords: Cancer; DNAJB12; ER stress; ERCYS; Spatial proteome; UPR

DOI: https://doi.org/10.1186/s11658-026-00875-2

J Mol Cell Cardiol. 2026 Feb 18. pii: S0022-2828(26)00021-0. [Epub ahead of print]

PERK retains a predominantly monomeric state under ER stress conditions.

Konstantina Georgoula, Luo Liu, Simone Jung, Iqra Sohail, Paolo Annibale, Gabriele G Schiattarella.

The unfolded protein response (UPR) is a central adaptive mechanism that safeguards protein homeostasis in the endoplasmic reticulum (ER). In the heart, UPR signaling contributes to cellular remodeling and survival across a range of pathological contexts, including ischemia, pressure overload, and cardiometabolic stress. Among the three canonical UPR branches, the PKR-like ER kinase (PERK) pathway plays a critical role in modulating translational control and redox balance during stress adaptation. Despite its functional importance, the molecular dynamics of PERK activation and assembly remain incompletely understood. Here, we investigate the oligomerization behavior of PERK in living cells using advanced fluorescence microscopy. We identify a concentration-dependent mechanism of PERK self-association, as well as a distinct population of oligomeric PERK whose assembly state remains stable upon ER stress induction. These findings challenge the traditional view of stress-induced oligomerization as a prerequisite for PERK activation and suggest the existence of non-canonical modes of PERK assembly with potential regulatory significance.

Keywords: Cardiomyocytes; Molecular brightness; Oligomerization; PERK; Unfolded protein response

DOI: https://doi.org/10.1016/j.yjmcc.2026.02.005

Bioorg Chem. 2026 Feb 13. pii: S0045-2068(26)00155-0. [Epub ahead of print]173 109619

Advances in the designing endoplasmic reticulum-targeted fluorescent probes.

Merve İnel, Ayse Yildirim, Bahadir Ozturk, Mustafa Yilmaz.

The endoplasmic reticulum (ER) plays a vital role in protein folding, lipid metabolism, and calcium homeostasis, and its dysfunction is implicated in a wide range of pathologies, including cancer, neurodegenerative diseases, and metabolic disorders. Recent advances in molecular imaging and chemical biology have enabled the development of ER-targeted fluorescent probes to monitor distinct physicochemical parameters and biological processes within this organelle. This review complements existing articles by organizing ER-targeted probes primarily according to targeting strategy and structure-activity relationships, rather than by probe type or analyte alone and categorises these probes into six basic functional groups: (i) peptid linked probes, (ii) enzyme specific probes (iii) reactive oxygen species (ROS) probes, (iv) viscosity-sensitive probes, (v) probes for ER morphology and identity, (vi) biosensors developed for specific disease contexts.

Keywords: ER stress; ER-targeted probes; Fluorescent biosensors; Organelle imaging

DOI: https://doi.org/10.1016/j.bioorg.2026.109619

J Clin Invest. 2026 Feb 19. pii: e196819. [Epub ahead of print]

Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice.

Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang Lin, Jiwon Hwang, Xinxin Chen, Alan C Rupp, Abigail J Tomlinson, Andrew J Scott, Zhen Zhao, Daniel R Wahl, Martin Myers, Costas A Lyssiotis, Ling Qi.

Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice (Sel1LSynCre) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age-mirroring core clinical features observed in affected patients-despite preserved neuronal numbers and only modest ER stress. Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulted from induction of the integrated stress response (ISR). Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing new insight into the molecular basis of ERAD-related neurodevelopmental disease.

Keywords: Cell biology; Cell stress; Metabolomics; Mouse models; Neuroscience

DOI: https://doi.org/10.1172/JCI196819

Immunity. 2026 Feb 18. pii: S1074-7613(26)00035-X. [Epub ahead of print]

The transcriptional repressor Fli1 inhibits proteostasis during nutrient stress to limit NK cell persistence in solid tumors.

Jeong Hyun Ji, Wesley R Armstrong, Joey H Li, Areeba Lalani, Cassidy D Lee, Varchas Bharadwaj, Kenneth Ho, Jingtong Liang, Alexander Muir, Timothy E O'Sullivan.

Tumor-infiltrating natural killer (NK) cells display reduced persistence and effector functions. Here, we examined the mechanisms underlying NK cell dysfunction in cancer. Gene expression analyses of matched tumor-infiltrating and tumor-adjacent human NK cells revealed that regulators of proteostasis were associated with worse survival outcomes. In mice, NK cells accumulated intracellular protein aggregates within 24 h of tumor infiltration. Nutrient stress in the tumor microenvironment (TME) triggered proteostasis imbalance in primary human NK cells, decreasing translation of cytokine receptors and inhibiting NK cell activation. SCENIC regulon and multiomic analyses identified FLI1 as a transcriptional repressor of the unfolded protein response (UPR) in NK cells. FLI1 induction following IL-15 signaling suppressed pro-survival UPR gene expression, limiting human NK cell proteostasis and intra-tumoral persistence. Fli1 deletion reduced protein aggregates and enhanced NK cell-mediated tumor control in vivo. Thus, the TME metabolome induces NK cell dysfunction through proteostasis imbalance, and FLI1 targeting may enhance NK cell anti-tumor function.

Keywords: Fli1; dysfunction; metabolism; natural killer cells; protein aggregate; proteostasis; solid tumors; tumor interstitial fluid; tumor microenvironment; unfolded protein response

DOI: https://doi.org/10.1016/j.immuni.2026.01.017

Front Immunol. 2026 ;17 1744197

Multi-omics analyses related to unfolded protein response in prostate cancer implicate pro-tumor role of IFRD1.

Yifeng Xue, Enyao Huang, Caichen Luo, Yanrong Qian, Tiange Wu, Chunyan Chu, Fan Shi, Shengrong Chen, Dakun Zhang, Weijun Chen, Weihua Huang, Ping Wang, Huixing Chen, Yifei Cheng, Yunxia Fan.

Introduction: The unfolded protein response (UPR) promotes prostate cancer (PCa) progression, yet its multi-omics landscape and clinical utility remain undefined.
Methods: We integrated single-cell and bulk transcriptomic datasets, and identified UPR-related genes (UPRRGs) through a combination of differential expression analysis and weighted gene co-expression network analysis (WGCNA), based on which we further developed a consensus UPR-related signature (UPRRS) using a machine learning framework. The UPRRGs were further characterized by functional enrichment, cell-cell communication, and survival analyses. A clinically applicable nomogram integrating UPR-related prognostic genes was constructed for prognostic prediction. Through in silico and in vitro analyses, we validated the clinical relevance between the hub UPRRGs and PCa progression.
Results: Single-cell analyses revealed elevated UPR activity in prostate epithelial cells, most prominently within the LE-KLK3 subpopulation. These cells exhibited enhanced ligand-receptor interactions in TNF, VEGF and NOTCH signaling axes. A seven-UPRRG signature (including IFRD1, DDIT3, HSPA5) demonstrated robust prognostic performance in the TCGA training set and three external validation cohorts (C-index > 0.82; AUC > 0.80). Multivariate Cox analysis confirmed UPRRS as an independent prognostic factor beyond clinical stage and Gleason score. Mechanistically, the UPRRS-high subgroup displayed an immunosuppressive microenvironment and reduced sensitivity to multiple chemotherapeutics. In vitro knock-down of IFRD1 markedly attenuated PCa cell proliferation and migration.
Conclusion: We provide the first systematic single-cell atlas of UPR heterogeneity in PCa and develop a clinically translatable UPRRS prognostic model. IFRD1, a key driver, emerges as a dual diagnostic and therapeutic target, offering both theoretical and experimental foundations for precision stratification and individualized management of PCa.

Keywords: IFRD1; UPR; prognostic biomarker; prostate cancer; scRNA-seq; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1744197