bims-unfpre 2026-09-27 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–09–27
twelve papers selected by
Susan Logue, University of Manitoba

Adenovirus early proteins E1A and E3-19K reveal separable regulatory states of the ER stress sensor IRE1a.
Apollo-IRE1: A Genetically Encoded Sensor for Live Cell and Multiplexed Imaging of Endoplasmic Reticulum Stress.
Influence of Endoplasmic Reticulum Stress on Urokinase Plasminogen Activation.
An Evolutionarily Conserved Ypk1/SGK1 Kinase Pathway Regulates the Unfolded Protein Response by Modulating the Ire1 Protein Abundance.
Loss of ceramide synthases 5 and 6 exacerbate myristate-induced colonic IRE1α activation.
Rift Valley fever virus virulence factor NSs targets ATF4- and XBP1-driven unfolded protein response.
Subtlety is underrated: Physiological UPR activation in meiosis.
IRE1α Is Associated with Host Lipid Biosynthesis During Human Coronavirus OC43 Infection.
Atherosclerotic Cell Fates: A Single-Cell View of ER Stress.
Ceapin-A7 Suppresses UPR Signaling and Mitigates Retinal Neovascularization in Vldlr-/- Mice.
Eggerthella lenta disrupts the gut vascular barrier to drive colorectal cancer liver metastasis.
IRE1α-XBP1s signaling links lipid homeostasis to hypoxic maladaptation and KRAS inhibitor responses in pancreatic ductal adenocarcinoma.

Mol Biol Cell. 2026 Sep 24. mbcE26060273

Adenovirus early proteins E1A and E3-19K reveal separable regulatory states of the ER stress sensor IRE1a.

Debkanya Sengupta, Shikha Srivastava, Fedor Bezrukov, Silvio Hemmi, Urs F Greber, Vibhu Prasad.

The unfolded protein response (UPR) controls cellular homeostasis and virus infections. It is canonically initiated by dissociation of ER chaperone BiP/GRP78 from lumenal domains of transmembrane sensor proteins, including the central UPR sensor inositol-requiring enzyme 1 alpha (IRE1a). This results in IRE1a activation and splicing of X-box binding protein 1 (XBP1) mRNA, leading to transcriptional activation of XBP1 for cellular adaptation and sustained infection. Human adenovirus (AdV) preferentially activates the IRE1a-XBP1 pathway through the viral membrane protein E3-19K, yet the mechanisms underlying this selective activation remain unclear. Here, we show that AdV uses two distinct early proteins to dissociate BiP from IRE1a and activate IRE1a-mediated XBP1 splicing. The immediate early protein E1A forms a complex with the cytoplasmic domain of IRE1a, sufficient to dissociate BiP from IRE1a without inducing XBP1 splicing or UPR activation. In contrast, E3-19K is expressed downstream of E1A, associates with the lumenal domain of IRE1a, and induces XBP1 splicing without promoting BiP dissociation from IRE1a. Both proteins were detected in IRE1a-containing complexes, consistent with stepwise viral regulation. Together, our findings show that canonical IRE1a activation hallmarks can be mechanistically separated during viral infection, revealing distinct AdV-regulated IRE1a activation states with discrete upstream and downstream signaling outputs.

DOI: https://doi.org/10.1091/mbc.E26-06-0273
ACS Sens. 2026 Sep 21.

Apollo-IRE1: A Genetically Encoded Sensor for Live Cell and Multiplexed Imaging of Endoplasmic Reticulum Stress.

Eric J Floro, Alex M Bennett, Romario Regeenes, Huntley H Chang, Nitya Gulati, Kenneth K Y Ting, Jonathan V Rocheleau.

  Pancreatic beta cells face exceptional protein folding demands from high insulin production requirements, placing extraordinary stress on the endoplasmic reticulum (ER) and contributing to dysfunction in diabetes pathogenesis. Monitoring ER stress dynamics in living cells remains challenging due to the destructive nature of traditional biochemical methods and the limitations of existing fluorescent sensors. Here, we present Apollo-IRE1, a genetically encoded sensor that reports on stress-induced IRE1 oligomerization and associated change in homoFRET via changes in fluorescence anisotropy. Apollo-IRE1 provides a ratiometric, intensity-independent readout, resulting in low day-to-day variability and a minimal spectral bandwidth, enabling multiplexed imaging alongside other cellular parameters. Photobleaching and enhancement curve analysis show that Apollo-IRE1 exists in apparent monomeric, dimer-range, and higher-order oligomeric states corresponding to baseline, moderate, and terminal ER stress conditions. The sensor also responds rapidly to chemical and physiological ER stressors in both immortalized beta-cell lines and primary mouse islet cells. These data establish Apollo-IRE1 as a practical tool for investigating ER stress dynamics in beta cells and other contexts where longitudinal single-cell measurements are essential.

Keywords:  BiP/GRP78; ER stress; IRE1; TXNIP; fluorescence anisotropy; homoFRET; live-cell imaging; pancreatic beta cells; protein oligomerization; unfolded protein response (UPR)

DOI:  https://doi.org/10.1021/acssensors.6c01159
Biomolecules. 2026 Aug 26. pii: 1235. [Epub ahead of print]16(9):

Influence of Endoplasmic Reticulum Stress on Urokinase Plasminogen Activation.

Diana Culej Bošnjak, Doris Janjić, Petra Korać, Mariastefania Antica, Maja Matulić.

  The urokinase plasminogen activator or urokinase is a highly specific extracellular protease involved in numerous physiological and pathological processes. Its activity is a consequence of its interplay with its inhibitor, PAI1, and receptor, uPAR, and is finely regulated at several levels. The aim of the work was to investigate whether endoplasmic reticulum stress can modulate urokinase activity. Two tumor cell lines grown in cell culture were treated with Thapsigargin and sodium salicylate, inducers of ER stress response. Urokinase activity was determined in the conditioned media, and expression of uPA system molecules and molecules involved in response to ER stress in cell lysates was measured. ER stress influenced urokinase activity: while in the glioblastoma line its activity was increased, in breast cancer cells it was decreased. Differences in activity were a consequence of urokinase and PAI1 expression at the protein and RNA level. However, ER stress decreased cell migration, invasion, and proliferation regardless of the changes in urokinase activity. Gene expression analysis indicated that cell specific activation of some transcription factors and pathways could be responsible for different urokinase activity regulation.

Keywords:  endoplasmic reticulum stress; plasminogen activator inhibitor; sodium salicylate; thapsigargin; urokinase plasminogen activator

DOI:  https://doi.org/10.3390/biom16091235
bioRxiv. 2026 Sep 18. pii: 2026.09.11.751087. [Epub ahead of print]

An Evolutionarily Conserved Ypk1/SGK1 Kinase Pathway Regulates the Unfolded Protein Response by Modulating the Ire1 Protein Abundance.

Saswata Chakrabarty, Anish Chakraborty, Jagadeesh Kumar Uppala, Noelle Marie Bryan, Nadege Gouignard, Nicholas J Reiter, An-Phu Tran, Madhusudan Dey.

The unfolded protein response (UPR) is a cellular mechanism that maintains protein homeostasis (proteostasis) under conditions of endoplasmic reticulum (ER) stress. The dual kinase/RNase Ire1 is a conserved regulator of the UPR, mediating the unconventional cytosolic splicing of HAC1 mRNA in yeast and XBP1 mRNA in human cells. The resulting spliced HAC1/XBP1 transcript encodes a transcription factor that induces the expression of protein-folding chaperones and stress-responsive genes, thereby restoring proteostasis. In our previous work, we showed that the MAP kinase Slt2 (homolog of human ERKs) contributes to UPR signaling by promoting IRE1 expression through the transcription factor Rlm1 (homolog of human MEF2C). Here, we demonstrate that Hac1 expression is reduced in yeast strains deficient in essential protein kinase Cdc28, Pkc1, Rio2, Tor2, Pkh1, or Ypk1, suggesting that these kinases also serve as UPR regulators. We focused on the kinase Ypk1, the yeast ortholog of human SGK1 (serum/glucocorticoid-regulated kinase 1). We provide genetic and biochemical evidence that Ypk1/SGK1 acts upstream of the Pkc1/PKCδ signaling pathway and is required for maintaining IRE1 protein abundance in both yeast and human cells. Collectively, our results identify an evolutionarily conserved Ypk1/SGK1 signaling pathway that regulates the HAC1 and XBP1 mRNA splicing by modulating the Ire1 protein abundance.

DOI: https://doi.org/10.64898/2026.09.11.751087
J Lipid Res. 2026 Sep 23. pii: S0022-2275(26)00189-6. [Epub ahead of print] 101159

Loss of ceramide synthases 5 and 6 exacerbate myristate-induced colonic IRE1α activation.

Chelsea L Doll, Mary R Gordon, Marco Padilla-Rodriguez, Eugene Jap, Paul A Boasiako, Marilyn T Marron, Brandon K Dahl, Keila S Espinoza, Drew M Seiser, Rachel J Ren, Curtis A Thorne, Justin M Snider, Ashley J Snider.

  High-fat diets (HFDs) are a major modifiable risk factor for intestinal health. Current research focuses primarily on palmitate (C16:0); however, myristate (C14:0, rich in dairy products) has been minimally investigated. HFDs increase ceramide generation which drives endoplasmic reticulum (ER) stress; with both sphingolipids and ER stress being key contributors to intestinal biology. Whether different fatty acids uniquely impact sphingolipid metabolism and ER stress in intestinal biology has not been well defined. Human colon epithelial cells were utilized to determine the role of ceramide synthases (CerS) 5 and 6 on myristate-induced ER stress using pharmacologic inhibitors and siRNA. Intestinal epithelial cell specific CerS5 and/or CerS6 knockout mice of both sexes were fed a control, high milk-fat, or high lard-fat diet for 16 weeks. Cells and colon tissues were analyzed for lipids, mRNA, and protein. Myristate treatment increased d18:1/C14:0-ceramide and induced IRE1α-dependent ER stress. Inhibition of CerS suppressed these effects, yet knockdown of CerS5/6, the primary enzymes generating d18:1/C14:0-ceramide, unexpectedly exacerbated IRE1α activation both in vitro and in vivo, potentially due to depletion of dihydro(dh)sphingosine. Altogether, our data suggest that loss of CerS5/6 exacerbate myristate-induced intestinal ER stress in colon epithelial cells and in vivo and accumulation of dhsphingosine may provide protection.

Keywords:  Ceramide Synthase; ER Stress; High-Fat Diet; Inflammatory Bowel Disease; Sphingolipids

DOI:  https://doi.org/10.1016/j.jlr.2026.101159
J Virol. 2026 Sep 24. e0123326

Rift Valley fever virus virulence factor NSs targets ATF4- and XBP1-driven unfolded protein response.

Kaori Terasaki, Shinji Makino.

  Rift Valley fever virus (RVFV) is a mosquito-borne arbovirus that infects humans and domestic ruminants, significantly impacting public health and the economy in African and Middle Eastern countries. RVFV non-structural protein NSs is a major viral virulence factor and possesses multiple functions to counteract host antiviral responses. One of its functions is to block host transcription by promoting degradation of subunits of the host transcription factor IIH (TFIIH). However, the biological significance of this function in the RVFV life cycle remains unclear. We used RVFV strain MP-12 and its mutant lacking the TFIIH degradation function (NSs-mut virus) to identify host genes targeted by NSs-mediated transcription suppression. We found that NSs-mut virus, but not MP-12, upregulated unfolded protein response (UPR) target genes compared to uninfected cells. Both viruses activated all three ER stress sensors, including PERK and IRE1. However, only MP-12 inhibited the PERK and IRE1 pathways by inhibiting the expression of their respective downstream mediators ATF4 and XBP1. ATF4 expression was inhibited at the transcriptional level, whereas XBP1 expression was inhibited at the post-transcriptional level. ATF4 depletion negatively impacted virus titer and the production of non-plaque-forming particles, resulting in alteration of the particle-to-PFU ratio of the viruses. We also showed that activation of the PERK pathway plays a pro-survival role in NSs-mut virus-infected cells, suggesting the involvement of the PERK pathway in RVFV-induced cytotoxicity. Taken together, our study revealed that RVFV NSs inhibits two out of the three UPR pathways and promotes RVFV-induced cytotoxicity by inhibiting the PERK pathway.IMPORTANCEThe Rift Valley fever virus (RVFV) NSs protein is a major virulence factor with multiple functions, including inhibition of general host transcription. RVFV carrying a mutated NSs that lacks the transcription suppression function is less cytotoxic in vitro and less virulent in mice compared to its parental virus, suggesting that NSs-mediated host transcription suppression is important for RVFV virulence. Experiments using this mutant virus and its parental RVFV revealed that NSs inhibits the expression of unfolded protein response (UPR) mediators ATF4 and XBP1, which act downstream of the PERK and IRE1 pathways, respectively. Our data also showed that activation of PERK promotes cell survival in RVFV infection. These data suggest that the NSs-mediated inhibition of UPR pathways contributes to RVFV pathogenicity.

Keywords:  NSs protein; Rift Valley fever virus; unfolded protein response

DOI:  https://doi.org/10.1128/jvi.01233-26
J Cell Biol. 2026 Oct 05. pii: e202608015. [Epub ahead of print]225(10):

Subtlety is underrated: Physiological UPR activation in meiosis.

David Pincus, Vladimir Denic.

In this issue, Bartolutti et al. (https://doi.org/10.1083/jcb.202509100) identify a physiological function for the unfolded protein response (UPR). The UPR has long been viewed as a coping mechanism for protein misfolding in the endoplasmic reticulum (ER). The authors here show that budding yeast naturally use this response to reorganize their ER during meiosis and sporulation, suggesting an ancient origin for the UPR as an adaptive developmental program.

DOI: https://doi.org/10.1083/jcb.202608015
Viruses. 2026 Sep 10. pii: 996. [Epub ahead of print]18(9):

IRE1α Is Associated with Host Lipid Biosynthesis During Human Coronavirus OC43 Infection.

Kaitlin N James, Jennifer A Miller, Hanna C Huston, Jessica M Oda, Susan L Fink.

  Research into the replication of human coronaviruses has surged, but much remains unknown regarding the host factors that influence disease. These viruses often activate cellular endoplasmic reticulum (ER) stress responses, benefiting from incompletely understood downstream effects. In this study, we investigated the role of the host ER stress response component, inositol-requiring enzyme 1 α (IRE1α), in regulating lipid metabolism during human coronavirus OC43 (HCoV-OC43) infection. We found IRE1α-dependent induction of lipogenesis-related genes, increased metabolic intermediates, and enhanced lipophilic membrane staining during infection. Inhibition of de novo fatty acid synthesis impaired HCoV-OC43 replication, while bypassing the first steps in de novo lipogenesis with supplementation of exogenous palmitate restored viral replication in the setting of IRE1α inhibition. Together, these results suggest that lipid metabolic remodeling is associated with IRE1α signaling during coronavirus infection and targeting these host pathways may represent a potential antiviral strategy.

Keywords:  ER stress; IRE1α; coronavirus; lipid; metabolism; unfolded protein response

DOI:  https://doi.org/10.3390/v18090996
J Cardiovasc Dev Dis. 2026 Sep 03. pii: 435. [Epub ahead of print]13(9):

Atherosclerotic Cell Fates: A Single-Cell View of ER Stress.

Shuyi Li, Xiang Lu.

  The role of endoplasmic reticulum (ER) stress in atherosclerosis has long been recognized, but whether it acts as a uniform pathological signal across all cell types has remained unclear. With the advancement of single-cell sequencing technology (scRNA-seq), we can analyze this problem at the resolution of a single cell subpopulation. In this review, we have synthesized the recent evidence from single-cell studies and proposed the "cell type-specific differential response" mode. We believe that endoplasmic reticulum stress does not universally have a pro-atherosclerotic effect. On the contrary, it shows a differential pattern in different atherosclerotic-related cell subpopulations. For example, endoplasmic reticulum stress is activated in monocytes but inhibited in certain macrophage subsets and endothelial cell subsets and dynamically regulated during phenotypic transitions in smooth muscle cells. We explored the underlying mechanisms of this heterogeneity, its impact on plaque progression, and the theoretical basis of subpopulation targeted treatment strategies. Ultimately, we concluded that recognizing the cellular heterogeneity of endoplasmic reticulum stress is the foundation for understanding and precisely intervening in atherosclerotic diseases.

Keywords:  ER stress; atherosclerosis; macrophage; scRNA-seq

DOI:  https://doi.org/10.3390/jcdd13090435
FASEB J. 2026 Sep 30. 40(18): e72300

Ceapin-A7 Suppresses UPR Signaling and Mitigates Retinal Neovascularization in Vldlr-/- Mice.

Soyoung Park, Angela Galdamez, William Temme, Allyssa Bradley, Masako Le, Leon Chea, Ethan Stevenson, Yudith Gradilla, Eun-Jin Lee, Jonathan H Lin.

  Pathological neovascularization drives blinding retinal diseases, including diabetic retinopathy, retinopathy of prematurity, and neovascular age-related macular degeneration. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling are key mechanisms underlying neovascularization. Mice lacking the UPR regulator Activating Transcription Factor 6 (ATF6) show normal retinal vasculature yet are resistant to pathologic neovascularization, suggesting that ATF6 inhibition may mitigate retinal damage and vision loss from aberrant retinal angiogenesis. We tested Ceapin-A7, a selective ATF6 inhibitor, in Vldlr-/- mice, a genetic model of retinal neovascularization. Intravitreal Ceapin-A7 reduced ectopic vascular projections into the outer retina and significantly increased scotopic b-wave amplitude, while a-wave and photopic responses showed no significant difference between groups. Single-nucleus RNA sequencing revealed suppressed ATF6/UPR gene programs and angiogenic pathways in retinal endothelial cells and reduced Müller cell gliosis. These findings demonstrate that pharmacologic ATF6 inhibition mitigates retinal neovascularization in Vldlr-/- mice and identifies ATF6/UPR as a therapeutic target for neovascular retinal diseases.

Keywords:  ATF6; UPR; VLDLR; neovascularization; retina; small molecule

DOI:  https://doi.org/10.1096/fj.202603175R
Cell Discov. 2026 Sep 22. pii: 67. [Epub ahead of print]12(1):

Eggerthella lenta disrupts the gut vascular barrier to drive colorectal cancer liver metastasis.

Cheng Kong, Yutao Jin, Guang Liu, Yangyang Guo, Fanying Guo, Yanlei Ma.

Distant metastasis is the leading cause of death in colorectal cancer (CRC), and the gut vascular barrier (GVB) is the first obstacle to hematogenous spread. To investigate whether GVB function is directly influenced by metastasis-associated bacteria, we analyzed two cohorts comprising 20 healthy controls, 82 non-metastatic CRC patients, and 65 patients with liver or lung metastases. Multi-omics approaches (metagenomic sequencing and single-cell RNA sequencing) and gnotobiotic mouse models were employed to examine gut microbes that are linked to GVB disruption and metastasis. Patients with CRC liver metastasis exhibited impaired GVB and bacterial colonization at metastatic sites. Eggerthella lenta was enriched in patients with elevated expression of plasmalemmal vesicle-associated protein-1 (PV-1), a GVB injury marker, and its abundance was correlated with metastasis and recurrence. In vitro and in vivo, E. lenta compromised endothelial tight junction and GVB integrity, enhancing CRC cell migration and liver metastasis. Mechanistically, E. lenta adhered to endothelial cells and activated endoplasmic reticulum (ER) stress via a TLR4-dependent pathway, promoting autophagy and apoptosis. The knockdown of PERK attenuated ER stress, prevented autophagy and apoptosis, and downregulated the expression of ZO-1 and Claudin-5 induced by E. lenta. These findings highlight the clinical potential of microbiota-targeted strategies and PERK inhibition in the treatment of E. lenta-associated CRC metastasis.

DOI: https://doi.org/10.1038/s41421-026-00922-4
Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2612523123

IRE1α-XBP1s signaling links lipid homeostasis to hypoxic maladaptation and KRAS inhibitor responses in pancreatic ductal adenocarcinoma.

Yanqing Jiang, Cassidy Pagen, Gusangyu Yin, Zian Zhang, Mai Wang, Carson D Poltorack, Yizheng Xue, Xu Han, Nathan J Coffey, Morgan Brown, Xuanyan Cai, Laura C Kim, Justin M Berg, Chih-Hang Anthony Tang, Yihui Shen, Brian Keith, Chih-Chi Andrew Hu, M Celeste Simon.

  Pancreatic ductal adenocarcinoma (PDAC) is among the most hypoxic human tumors. Because fatty acid (FA) desaturation is oxygen-dependent, hypoxia can limit monounsaturated FA (MUFA) production, increase membrane lipid saturation, and activate endoplasmic reticulum stress responses, including IRE1α-XBP1s. Here, we found that under oxygen- and MUFA-limiting conditions, spliced XBP1 (XBP1s) is upregulated but unexpectedly exerts a cytotoxic rather than cytoprotective role in PDAC cells. This effect did not differ substantially between classical and basal subtypes. In contrast, pharmacologic or genetic XBP1s inhibition had limited effects on tumor growth and apoptosis in vivo, suggesting this cytotoxicity is largely bypassed by factors in the tumor microenvironment. Consistent with our previous findings that cancer-associated fibroblasts supply unsaturated lipids to tumor cells, subcutaneous tumors showed abundant alpha-smooth muscle actin (α-SMA)-positive stroma, supporting the possibility that stromal lipid supply protects tumors from XBP1s-dependent lipotoxicity. Although XBP1s expression increased during PDAC progression, its distribution remained focal and heterogeneous within human tumors, suggesting spatially restricted IRE1α-XBP1s pathway activation that may limit the efficacy of monotherapy in patients. However, MRTX1133-resistant PDAC became more susceptible to IRE1α-XBP1s targeting, and MRTX1133 acutely activated this pathway in parental cells upon treatment. Importantly, the IRE1α RNase inhibitor B-I09 clearly synergized with MRTX1133 in vitro and in vivo, moreover, this is likely due to MYC-fatty acid synthase (FASN) dysregulation. Together, these findings identify context-dependent vulnerabilities of the IRE1α-XBP1s pathway in PDAC and provide a rationale for combining inhibition of IRE1α and KRAS to enhance therapeutic responses.

Keywords:  ER stress responses; KRAS inhibitors; hypoxia; lipid metabolism

DOI:  https://doi.org/10.1073/pnas.2612523123