bims-unfpre 2026-03-08 papers

Issue of 2026–03–08
five papers selected by
Susan Logue, University of Manitoba

Cell Stress Chaperones. 2026 Feb 27. pii: S1355-8145(26)00019-2. [Epub ahead of print] 100163

Activation of Unfolded Protein Response Pathways Promotes Keratinocyte Differentiation and Ameliorates Psoriasis Phenotypes.

Zhibao Zhang, Mingyi Tan, Xin Liu, Wenhua Wang, Xiang Chen, Cong Peng, Shuang Zhao, Lisha Wu.

Psoriasis is a chronic inflammatory skin disorder characterized by abnormal keratinocyte (KC) differentiation and proliferation, along with infiltration of various immune cells into the skin. Both internal and external perturbations can disrupt endoplasmic reticulum (ER) homeostasis, leading to ER stress and activation of the unfolded protein response (UPR) pathways. Although the UPR is known to participate in normal epidermal KC differentiation, its regulatory role in psoriasis remains poorly understood. In this study, we observed significant attenuation of UPR pathways specifically IRE1α-XBP1s and PERK signaling in psoriasis lesions. Administration of ER stress inducers (TM and BFA) alleviated psoriasis-like phenotypes in an imiquimod (IMQ)-induced mouse model. Furthermore, knockdown of Grp78 in KCs activated both IRE1α-XBP1s and PERK pathways, thereby improving KC differentiation in vitro. Notably, combining of Grp78 knockdown with ER stress inducers synergistically enhanced KC differentiation through UPR activation. Together, these findings indicate that the ER stress response promotes epidermal KC differentiation. Targeted activation of UPR pathways may thus represent a novel therapeutic strategy to improve KC differentiation in psoriasis.

Keywords: Endoplasmic Reticulum stress; Keratinocyte differentiation; Psoriasis; Unfolded Protein Response

DOI: https://doi.org/10.1016/j.cstres.2026.100163

iScience. 2026 Mar 20. 29(3): 114818

Tet2 modulates ER stress responses related to β-cell death and autoimmunity in diabetes.

Jinxiu Rui, Madhav Kothari, Romy Kursawe, Mahsa Nouri Barkestani, Romi Genosar, Pamela Clark, Michael L Stitzel, Kevan C Herold.

We found that beta cells from Tet2-deficient mice were protected from killing in a model of autoimmune Type 1 diabetes, but the mechanism of protection and specific cell types affected by Tet2 loss were unknown. Herein we show that in Tet2-deficient NOD mice transplanted with wild-type bone marrow, there are fewer islet infiltrating lymphocytes beginning 8-10 weeks after transplant, which was seen primarily among CD4+ T-cells. Transcription factor binding motifs for interferon responses factors and inflammatory signaling molecules were enriched in Tet2-responsive cis-regulatory elements across all KO islet endocrine cells, but we observed beta cell-specific enrichment of TFs modulating homeostatic or ER stress response pathways. To determine whether there were similar effects in human islets, we induced ER stress with brefeldin A or thapsigargin and inhibited TET2 with Bobcat 339. Pharmacologic TET inhibition reduced expression of ER stress response genes, inflammatory responses, and stress-induced beta cell death. We conclude that Tet2 (TET2) can regulate ER stress responses involved in beta cell killing in autoimmune/inflammatory settings.

Keywords: cell biology; immunology; molecular biology

DOI: https://doi.org/10.1016/j.isci.2026.114818

J Biol Chem. 2026 Feb 26. pii: S0021-9258(26)00203-6. [Epub ahead of print] 111333

Brucella Omp25 activates the unfolded protein response to promote intracellular proliferation and inflammation.

Jin-Ke Yang, Shuang Huang, Yuan-Pan Hou, Hui-Fei Yuan, Yue Wang, Mi Li, Li-Bo Cao, Tian Xia, Hong-Bing Shu, Xin Wu.

Brucellosis is a widespread zoonotic disease caused by Brucella, a genus of facultative intracellular bacteria that infects livestock and humans. Brucella primarily replicates within the endoplasmic reticulum (ER) of host cells, where it establishes a specialized replicative niche. This ER localization disrupts ER structure and induces ER stress. The unfolded protein response (UPR) is a critical cellular pathway that maintains ER homeostasis by restoring protein-folding capacity and regulating stress responses. However, how Brucella manipulates host UPR pathways to promote its intracellular survival and pathogenesis remains poorly understood. Here, we identify the Brucella outer membrane protein Omp25 as a key factor in promoting its intracellular survival and proliferation by activating the host UPR. Omp25 directly binds to the ER chaperone Binding-immunoglobulin protein (BiP), inducing the release and activation of the UPR sensors PERK (PKR-like ER kinase), IRE1α (inositol requiring enzyme 1 alpha), and ATF6 (activating transcription factor 6), thereby modulating ER homeostasis to favor bacterial replication. Additionally, Omp25 enhances inflammatory cytokine expression via the BiP-IRE1α-NF-κB signaling axis. The omp25-deleted strains (Δomp25) show impaired intracellular replication and reduced UPR activation, and result in attenuated induction of inflammatory genes in infected cells compared to wild-type strains. In vivo, mice infected with an omp25 mutant strain exhibit lower bacterial burdens and milder tissue pathology compared to mice infected with the wild-type strain. These findings uncover a mechanism by which Omp25 facilitates Brucella intracellular proliferation through UPR modulation and highlight Omp25 as a potential target for therapeutic interventions and next-generation attenuated vaccines.

Keywords: BiP; Brucella; Omp25; inflammation; unfolded protein response (UPR)

DOI: https://doi.org/10.1016/j.jbc.2026.111333

Oncogene. 2026 Mar 03.

Ginkgetin targets GRP78 to induce dual pathways of ER stress and immune activation in osteosarcoma.

Wenyuan Xu, Tongtong Liu, Xinglong Ma, He Dong, Yinghao Cao, Guanyi Li, Zhuoying Wang, Yingqi Hua, Zhengdong Cai, Mengxiong Sun, Jingjie Li, Tao Zhang.

Osteosarcoma is an aggressive malignancy characterized by rapid proliferation and a propensity for metastasis. The endoplasmic reticulum (ER) chaperone GRP78, a critical regulator of osteosarcoma progression, represents a promising therapeutic target. In this study, we identified the natural compound ginkgetin (Gink) as a novel GRP78 inhibitor. Cellular thermal shift assays, surface plasmon resonance, and mutagenesis studies revealed that Gink directly binds to GRP78, with K296 serving as a key interaction site. In vitro, Gink suppressed osteosarcoma cell proliferation, migration, and invasion while inducing apoptosis and autophagy by activating the PERK-eIF2α-ATF4 pathway. Co-immunoprecipitation assays showed that Gink competitively disrupted GRP78-PERK interaction. In orthotopic and patient-derived xenograft models, Gink treatment markedly attenuated tumor growth and metastasis. Gink also reprogrammed the tumor immune microenvironment by reducing M2 macrophage polarization and synergizing with anti-PD1 therapy to enhance CD8+ T-cell activity. Accordingly, Gink could be developed as a GRP78-targeting agent that triggers ER stress and immune activation, offering a dual-pronged therapeutic strategy against osteosarcoma. Ginkgetin (Gink) directly binds to GRP78 in a competitive manner, disrupting the interaction between GRP78 and PERK. This leads to PERK activation and phosphorylation, which in turn phosphorylates eIF2α to trigger ATF4 transcription. Ultimately, this cascade induces apoptosis and autophagy, inhibiting cancer progression. Additionally, Gink suppresses M2 macrophage polarization and enhances CD8+ T cell cytotoxicity, both of which contribute to the prevention of cancer development.

DOI: https://doi.org/10.1038/s41388-026-03704-0

Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2533457123

Inhibition of FicD-mediated AMPylation and deAMPylation by isoprenoid diphosphates.

Aubrie M Blevins, Wei Peng, Lisa N Kinch, Zihan Monshad, Andrea G Paredes, Christina Volz, Jared Rutter, Amanda K Casey, Kevin G Hicks, Kim Orth.

FicD regulates Unfolded Protein Response (UPR) through reversible AMPylation and deAMPylation of BiP, an HSP70 chaperone and master regulator of the UPR. FicD activity is regulated by endoplasmic reticulum-stress, catalyzing BiP AMPylation under low stress conditions to hold inactive chaperone in reserve. In stressed cells, FicD deAMPylates BiP, acutely increasing its active pool to assist in protein folding. Variants in UPR machinery, including those in the FicD gene, are linked to hereditary diseases. Despite the known role of FicD in UPR, in-vivo regulation of its activity remains elusive, and identifying metabolites that alter FicD activity could prove useful pharmaceutically. We applied an unbiased high-throughput screening platform, known as Mass spectrometry Integrated with equilibrium Dialysis for the discovery of Allostery Systematically (MIDAS), to identify small molecule metabolites that might regulate FicD activity. MIDAS revealed interactions between FicD and two mevalonate pathway intermediates: geranyl-pyrophosphate and farnesyl-pyrophosphate. Biochemical characterization indicates that both potently inhibit FicD-mediated AMPylation and deAMPylation. The crystal structure of FicD bound to farnesyl-pyrophosphate demonstrates a competitive inhibition mechanism, with the pyrophosphate adopting the alpha and beta phosphate positions of adenosine triphosphate (ATP) and the hydrocarbon chain filling the nucleoside pocket. FicD variants previously appeared as biochemically indistinguishable, yet lead to different human pathologies. We demonstrate farnesyl-pyrophosphate inhibits FicDR374H and FicDR374C variants implicated in causing hereditary spastic paraplegia, but not the FicDR371S variant associated with neonatal diabetes. This study furthers our understanding of FicD inhibitors and distinguishes disease causing variants, providing insight into pharmacological targeting of UPR activity.

Keywords: AMPylation; FicD; PTM; isoprenoid diphosphates; unfolded protein response

DOI: https://doi.org/10.1073/pnas.2533457123