bims-unfpre 2026-02-01 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–02–01
eight papers selected by
Susan Logue, University of Manitoba

ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.
Deciphering Roles of Placental Endoplasmic Reticulum Stress in Complicated Pregnancies and Beyond: The Power of Mouse Models.
NUSAP1 Drives Endometrial Carcinoma via IP3R Phosphorylation, Calcium Dyshomeostasis, and ER-Stress-Mediated Apoptosis.
Cultured cells activate IRE1 during attachment and flattening after routine passaging.
Inhibiting stearoyl-CoA desaturase suppresses bone metastatic prostate cancer by modulating cellular stress, mTOR signaling, and DNA damage response.
Sec61β maintains cytoplasmic proteostasis via ARIH1-mediated translational repression upon ER stress.
A New Perspective on Osteogenesis Imperfecta: From Cellular Mechanisms to the Systemic Impact of Collagen Dysfunction.
The dual face of reprogrammed proteostasis in cancer and its epigenetic regulation: A survival option and a therapeutic opportunity.

FEBS J. 2026 Jan 29.

ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.

Giorgia Maria Renna, Alessandro Cherubini, Ersilia Varone, Serena Germani, Alice Marrazza, Ester Zito.

  Proteostasis maintains the balance between protein synthesis, folding, and degradation within the endoplasmic reticulum (ER). This quality-control system ensures that proteins undergo proper post-translational modifications-such as PDI-ERO1-mediated oxidative folding and STT3-dependent N-glycosylation-so that only correctly folded proteins proceed through the secretory pathway. Impairment of protein load, folding capacity, or degradation via the ER-associated degradation (ERAD) pathway leads to the accumulation of unfolded proteins, triggering ER stress and activating the unfolded protein response (UPR), which, in the first instance, is an adaptive signaling network designed to restore homeostasis by adjusting protein synthesis, enhancing folding capacity, and promoting the clearance of misfolded proteins. During ER stress, the ER undergoes morphological and functional remodeling to manage the increased folding burden, including an increase of ER-mitochondria contact sites (ERMCs). These nanometric junctions (~10-100 nm) facilitate lipid and metabolite exchange and mediate calcium and reactive oxygen species signaling to support cellular metabolism. However, chronic ER stress can further tighten ERMCs, leading to calcium overload, mitochondrial dysfunction, and apoptosis. This review examines the core mechanisms underlying ER proteostasis in the context of ER stress and explores how ER stress first boosts mitochondrial activity and later impairs it through ERMCs, contributing to cell death and disease. Finally, emerging therapeutic strategies aimed at restoring proteostasis and modulating the dynamics of ERMCs are highlighted as promising interventions for conditions, such as cancer and congenital myopathies, where ER and mitochondrial dysfunction play central roles in pathogenesis.

Keywords:  ERMC; cancer; mitochondria metabolism; neuromuscular diseases; proteostasis

DOI:  https://doi.org/10.1111/febs.70431
Cells. 2026 Jan 06. pii: 96. [Epub ahead of print]15(2):

Deciphering Roles of Placental Endoplasmic Reticulum Stress in Complicated Pregnancies and Beyond: The Power of Mouse Models.

Hong Wa Yung, Yat Nam Yung, Graham J Burton, D Stephen Charnock-Jones.

  Over a quarter of human pregnancies are associated with complications, including fetal growth restriction, pre-eclampsia and gestational diabetes. These are major causes of maternal and fetal morbidity and mortality, and also lead to a 3-5-fold increased risk of subsequent development of cardio-metabolic diseases. Although the mechanistic details remain elusive, a dysfunctional placenta is central to the pathophysiology of these conditions. The placenta ensures sufficient nutrient supply to the fetus without compromising maternal wellbeing. This balance is achieved by the secretion of large quantities of placental-derived peptide hormones into the maternal circulation. Consequently, the placenta is susceptible to endoplasmic reticulum (ER) stress, and we were the first to demonstrate the presence of ER stress in placentas from complicated pregnancies. The mouse placenta provides an ideal model for studying the impact of ER stress as it is composed of two distinct regions, an endocrine zone and a transport zone. Therefore, perturbation of placental endocrine function by ER stress can be generated without directly affecting its capacity for nutrient exchange. In this review, we summarise the current literature on how transgenic mouse models enhance our understanding of ER stress-mediated perturbation of placental endocrine function, and its contribution to the pathophysiology of pregnancy complications and life-long health.

Keywords:  animal model; endoplasmic reticulum stress; fetal growth restriction; placenta; pre-eclampsia; pregnancy

DOI:  https://doi.org/10.3390/cells15020096
ACS Omega. 2026 Jan 20. 11(2): 2499-2512

NUSAP1 Drives Endometrial Carcinoma via IP3R Phosphorylation, Calcium Dyshomeostasis, and ER-Stress-Mediated Apoptosis.

Hongyan Xiao, Honghong Wang, Hui Yang, Fang Li, Lijun Ma, Hongyun Ma.

Nucleolar and spindle-associated protein 1 (NUSAP1), a mitotic regulator critical for cancer cell cycle progression, remains poorly characterized in endometrial carcinoma (EC). Here, we integrated bioinformatics analysis with functional assays, including flow cytometry, Transwell invasion, ER stress imaging (ER fluorescence probe), intracellular Ca2+ measurement (Fluo-4 AM), and Western blotting, to dissect the role of NUSAP1 role in EC. NUSAP1 was significantly overexpressed in EC tissues compared to normal controls. Strikingly, we identified a functional interaction between NUSAP1 and the inositol 1,4,5-trisphosphate receptor (IP3R), a key ER calcium release channel. Knocking down NUSAP1 suppressed EC cell proliferation and invasion while inducing mitophagy and apoptosis. These effects were accompanied by elevated cytosolic Ca2+ levels, exacerbated ER stress, and increased phosphorylated IP3R (p-IP3R). Conversely, NUSAP1 overexpression reciprocally attenuated these phenotypes. IP3R silencing alone reduced intracellular Ca2+ and ER stress without altering NUSAP1 expression, whereas NUSAP1 overexpression combined IP3R knockdown synergistically amplified these effects. Mechanistically, NUSAP1 governs IP3R phosphorylation to regulate Ca2+ homeostasis, ER stress, and mitophagy, thereby modulating apoptotic signaling in EC. Our study unveils the NUSAP1-IP3R axis as a central driver of EC progression, offering novel therapeutic targets for calcium-dependent oncogenic pathways.

DOI: https://doi.org/10.1021/acsomega.5c05485
MicroPubl Biol. 2026 ;2026

Cultured cells activate IRE1 during attachment and flattening after routine passaging.

Paige Dillon, Lincoln Hollingshead, Julie Hollien.

During endoplasmic reticulum (ER) stress, the ER membrane protein IRE1 initiates the regulated splicing of Xbp1 mRNA, leading to the production of a potent transcription factor that helps cells restore proteostasis. We report that Xbp1 is also spliced following the routine passaging of mouse MC3T3-E1 cells, without the addition of canonical ER stressors. This splicing was independent of the type of dissociation buffer used to release cells from the surface, but was reduced when cells were plated on non-adherent culture dishes. These findings suggest that certain cultured mammalian cells induce an unfolded protein response during reattachment and spreading after passaging.

DOI: https://doi.org/10.17912/micropub.biology.001968
FEBS Lett. 2026 Jan 28.

Inhibiting stearoyl-CoA desaturase suppresses bone metastatic prostate cancer by modulating cellular stress, mTOR signaling, and DNA damage response.

Alexis Wilson, Mackenzie K Herroon, Shane Mecca, Laimar C Garmo, Jacob Lindquist, Shrila Rajendran, Steve M Patrick, Izabela Podgorski.

  The mechanisms supporting progression of metastatic prostate cancer (PCa) in adipocyte-rich bone marrow remain unclear. We hypothesized that stearoyl-coenzyme A desaturase (SCD) promotes PCa survival in bone by modulating stress responses and regulating lipid peroxidation. We show that SCD-high PCa cells are sensitive to SCD loss, showing smaller spheroids, reduced mTOR signaling, and elevated endoplasmic reticulum (ER) stress. SCD expression is further augmented by adipocytes, and SCD loss induces DNA damage and repair activation only with adipocyte exposure. In vivo, pharmacological SCD inhibition reduces tumor size and increases ER stress and DNA damage in SCD-high-expressing bone tumors. These findings suggest SCD plays a role in redox regulation and DNA repair sensitivity, with therapeutic potential for targeting DNA repair pathways in combination with SCD inhibition. Impact statement This study reveals that stearoyl-CoA desaturase (SCD) supports prostate cancer growth in adipocyte-rich bone by regulating redox balance and DNA repair responses, uncovering a metabolic mechanism linking lipid metabolism to genomic stability and suggesting therapeutic potential for combining SCD and DNA repair pathway inhibition.

Keywords:  DNA damage; ER stress; bone marrow adipocytes; bone metastasis; lipid desaturation; prostate cancer; stearoyl CoA desaturase

DOI:  https://doi.org/10.1002/1873-3468.70290
EMBO Rep. 2026 Jan 27.

Sec61β maintains cytoplasmic proteostasis via ARIH1-mediated translational repression upon ER stress.

Hisae Kadowaki, Tomohisa Hatta, Kazuma Sugiyama, Tomohiro Fukaya, Takao Fujisawa, Takashi Hamano, Naoya Murao, Yasunari Takami, Shuya Mitoma, Tohru Natsume, Katsuaki Sato, Hiromi Hirata, Tamayo Uechi, Hideki Nishitoh.

  Disrupted proteostasis causes various degenerative diseases, and organelle homeostasis is therefore maintained by elaborate mechanisms. Endoplasmic reticulum (ER) stress-induced preemptive quality control (ERpQC) counteracts stress by reducing ER load through inhibiting the translocation of newly synthesized proteins into the ER for their rapid degradation in the cytoplasm. Here, we show that Sec61β, a translocon component, prevents the overproduction of ERpQC substrates, allowing for their efficient degradation by the proteasome. Sec61β inhibits the binding of translation initiation factor eIF4E to the mRNA 5' cap structure by recruiting E3 ligase ARIH1 and eIF4E-homologous protein 4EHP, resulting in selective translational repression of ERpQC substrates. Sec61β deficiency causes overproduction of ERpQC substrates and reduces proteasome activity, leading to cytoplasmic aggresome formation. We also show that Sec61β deficiency causes motor dysfunction in zebrafish, which is restored by exogenous ARIH1 expression. Collectively, translational repression of ERpQC substrates by the Sec61β-ARIH1 complex contributes to maintain ER and cytoplasmic proteostasis.

Keywords:  ER Stress; ERpQC; Proteostasis; Translational Regulation

DOI:  https://doi.org/10.1038/s44319-026-00690-y
Int J Mol Sci. 2026 Jan 12. pii: 745. [Epub ahead of print]27(2):

A New Perspective on Osteogenesis Imperfecta: From Cellular Mechanisms to the Systemic Impact of Collagen Dysfunction.

Emma Lugli, Ludovica Gaiaschi, Maria Grazia Bottone, Fabrizio De Luca.

  Osteogenesis imperfecta (OI) is a rare genetic disease caused by mutations in collagen type I, leading to defective protein folding and an impaired extracellular matrix structure and remodelling. Beyond skeletal fragility, these molecular defects trigger a network of intracellular stress responses with multiorgan implications: the accumulation of misfolded collagen can induce persistent endoplasmic reticulum stress, which can in turn compromise mitochondrial function and autophagy or lead to cell death activation, and it can even promote widespread redox imbalance and inflammation. The interplay between intracellular stress, widespread oxidative damage and inflammation not only underlies cellular dysfunction but also the multisystemic manifestations of osteogenesis imperfecta. Targeting these interconnected pathways may result in new insights for a better understanding of OI and possibly offer novel therapeutic strategies designed to restore proteostasis and improve cell homeostasis and overall patient outcomes, highlighting the need for an integrated understanding of the cellular and molecular mechanisms involved in the pathogenesis of this disease and their translation into patient-centred therapeutic interventions.

Keywords:  ER stress; autophagy; cell death; collagen dysfunction; in vivo models; intracellular stress; mitochondrial stress; osteogenesis imperfecta; redox imbalance; systemic inflammation

DOI:  https://doi.org/10.3390/ijms27020745
Biochim Biophys Acta Mol Cell Res. 2026 Jan 23. pii: S0167-4889(26)00012-1. [Epub ahead of print]1873(3): 120116

The dual face of reprogrammed proteostasis in cancer and its epigenetic regulation: A survival option and a therapeutic opportunity.

Mara Cirone.

  Proteostasis is essential for cellular homeostasis and is maintained through an integrated network encompassing the unfolded protein response (UPR), molecular chaperones such as heat shock proteins (HSPs), and degradative systems including the ubiquitin-proteasome and autophagy-lysosomal pathways. In cancer, microenvironmental stresses such as hypoxia, nutrient deprivation, and oxidative imbalance impose a persistent proteotoxic burden, driving a context-dependent rewiring of these pathways that supports tumor survival, plasticity, and progression. Increasing evidence indicates that the functional outcomes of proteostasis responses, whether adaptive or cytotoxic, are determined by specific molecular cues, including the intensity and duration of stress, pathway crosstalk, and cell-intrinsic oncogenic alterations. Epigenetic mechanisms, comprising DNA methylation, histone modifications, and non-coding RNAs, further fine-tune these proteostatic programs by modulating the expression and activity of key regulators, thereby contributing to drug resistance but also generating cancer-selective vulnerabilities. This review provides a structured and mechanistic overview of how UPR, chaperone networks, and protein degradation pathways are remodeled in cancer and examines the epigenetic determinants that shape their adaptive behavior. Finally, we discuss emerging translational opportunities arising from the dual role of proteostasis in cancer, highlighting therapeutic strategies that exploit the dynamic interplay between proteostatic and epigenetic regulation.

Keywords:  Autophagy; Cancer; Epigenetics; HSPs; UPR; UPS

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120116