bims-unfpre 2026-09-13 papers

Issue of 2026–09–13
six papers selected by
Susan Logue, University of Manitoba

PLoS Genet. 2026 Sep;22(9): e1012301

ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans.

Liying Guan, Tong Zhang, Zhigao Zhan, Yingchun Wang, Xun Huang, Mei Ding.

Disruption of endoplasmic reticulum (ER) homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Although defects in the secretory machinery can induce ER stress, whether specific trafficking components actively couple cargo handling to UPR signaling remains unclear. Here, using Caenorhabditis elegans genetics, imaging, and biochemical assays, we show that neuronal overexpression of the gap junction protein UNC-9 cell-autonomously activates the IRE-1-XBP-1 branch of the ER UPR. Loss of the early secretory pathway proteins ERGI-2 or ERGI-3 suppresses this response and disrupts UNC-9 localization, revealing functions for these proteins that extend beyond cargo trafficking. ERGI-2 and ERGI-3 interact with both UNC-9 and the ER chaperone HSP-4/BiP, suggesting that they couple the handling of excessive UNC-9 to UPR activation. This requirement is cargo-selective: ERGI-2 and ERGI-3 are dispensable for UPR activation induced by overexpression of another innexin, UNC-7, or unrelated proteins. Moreover, activation of the IRE-1-XBP-1 pathway reduces abnormal UNC-9 accumulation in ergi-2 and ergi-3 mutants. Together, our findings identify ER-to-Golgi trafficking proteins as cargo-selective regulators that link secretory-pathway demand to adaptive UPR.

DOI: https://doi.org/10.1371/journal.pgen.1012301

Cell Rep. 2026 Sep 10. pii: S2211-1247(26)01031-4. [Epub ahead of print]45(9): 117953

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Bingqing Zou, Qiuyun Chen, Junjun Zheng, Yimin Ma, Jay Myers, Yinghui Shang, Mofei Huang, Paul Christensen, Stanley Adoro, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Sai Ravi Kiran Pingali, Wei Xin, Keith Syson Chan, Stephen Wong, Youli Zu, Hamed Jafar-Nejad, Lan Zhou.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

Keywords: CP: cell biology; CP: developmental biology; DLL4; ER stress; IL7; MSC; NOTCH3; PERK; bone marrow endothelium

DOI: https://doi.org/10.1016/j.celrep.2026.117953

Cell Stress Chaperones. 2026 Sep 05. pii: S1355-8145(26)00070-2. [Epub ahead of print] 100212

Acupuncture Suppresses the ER Stress-JNK Pathway to Inhibit Chondrocyte Apoptosis and Attenuate Knee Osteoarthritis.

Renzhong Li, Minshun Zhu, Sanbing Wu, Kui Sun.

BACKGROUND: Knee osteoarthritis (KOA) is a degenerative joint disease characterized by progressive cartilage degradation, in which chondrocyte apoptosis plays a pivotal role. Acupuncture is widely used for KOA management, but its underlying molecular mechanisms remain poorly understood. Endoplasmic reticulum (ER) stress-induced apoptosis via the c-Jun N-terminal kinase (JNK) pathway is a critical driver of chondrocyte death in KOA. This study aimed to investigate whether acupuncture exerts its chondroprotective effects by modulating the ER stress-JNK signaling axis.
METHODS: A rat model of KOA was established by joint immobilization. Fifty rats were randomly assigned to five groups: Normal, Model, Model+Acupuncture (Acu), Model+ Acu+Anisomycin(JNK activator), and Model+SP600125(JNK inhibitor). The therapeutic efficacy of a 4-week acupuncture regimen was evaluated through behavioral scores, radiographic imaging, and histological analysis. Unbiased RNA-sequencing was performed to identify key signaling pathways. The mechanism was further validated through TUNEL staining, Transmission electron microscopy (TEM), Western blot, RTqPCR, immunofluorescence, and ELISA.
RESULTS: Unbiased transcriptomic analysis identified the ER stress and MAPK/JNK signaling pathways as key targets of acupuncture. Acupuncture significantly improved joint function, alleviated cartilage degradation, and preserved proteoglycan content in KOA rats. Mechanistically, acupuncture suppressed the expression of the ER stress marker IRE1α, inhibited the phosphorylation of JNK, and consequently downregulated the pro-apoptotic Bax/Bcl-2 ratio and Caspase-3 expression. This led to a marked decrease in chondrocyte apoptosis and restoration of ER homeostasis, as confirmed by TUNEL and TEM. Crucially, the anti-apoptotic effects of acupuncture were significantly counteracted by the JNK activator Anisomycin. In addition, acupuncture remodels the systemic inflammatory network by suppressing the production of proinflammatory cytokines IL-1β and TNF-α, which triggers a compensatory upregulation of the anti-inflammatory mediator IL-10.
CONCLUSION: Our findings demonstrate for the first time that acupuncture ameliorates knee osteoarthritis by inhibiting chondrocyte apoptosis via suppression of the ER stress-JNK signaling pathway. This study provides a novel and robust mechanistic rationale for the clinical application of acupuncture and highlights the ER stress-JNK axis as a promising therapeutic target for KOA.

Keywords: Acupuncture; Chondrocyte Apoptosis; Endoplasmic Reticulum Stress; JNK Signaling Pathway; Knee Osteoarthritis

DOI: https://doi.org/10.1016/j.cstres.2026.100212

Sci Adv. 2026 Sep 11. 12(37): eaeb1237

Magnetically actuated nanoantennas for wireless glioblastoma therapy.

Monochura Saha, Ishaq N Khan, Baju Joy, Shun-Ying Chen, Hao-Tung Yang, Preet Patel, Kyuho Jang, Pengrui Zhang, Faheem Azeemi, Deblina Sarkar.

Glioblastoma (GBM) remains a formidable clinical challenge, characterized by invasive growth, therapeutic resistance, and dismal patient survival. We report the development of HITMAN (highly localized electric field-induced tumor therapy using magnetically actuated nanoantennas), a wireless bioelectric therapy that selectively eradicates GBM cells with cellular precision. Magnetically actuated nanoantennas convert low-frequency (≤200 kHz), deep-brain-penetrant magnetic fields into localized electric fields, thereby triggering protein unfolding, membrane disruption, and ER stress. In vitro, HITMAN demonstrated superior efficacy compared to temozolomide (TMZ), significantly decreasing viability in drug-resistant, patient-derived GBM cells by 52.2%, versus 10% with TMZ while sparing neurons and astrocytes. Mechanistically, HITMAN activated the unfolded protein response and autophagy pathways, suppressed cell cycle and adhesion genes, reduced Ki-67 expression, disrupted cytoskeletal architecture, and elevated p53 levels, underscoring a multifaceted antitumor mechanism. In orthotopic mouse models, HITMAN significantly inhibited tumor growth, extended median survival by more than 50%, and exhibited no systemic toxicity. Thus, HITMAN offers a minimally invasive, spatially precise, and clinically translatable therapy for GBM.

DOI: https://doi.org/10.1126/sciadv.aeb1237

Stem Cell Reports. 2026 Sep 10. pii: S2213-6711(26)00289-4. [Epub ahead of print] 103078

Chemical induction and reversal of photoreceptor dystrophy in retinal organoids.

Allyssa Bradley, Hyejung Min, Soyoung Park, William Temme, Soyeon Park, Ahmad Al-Moujahed, Eun-Jin Lee, Jonathan H Lin.

Activating transcription factor 6 (ATF6) controls a signal transduction pathway of the unfolded protein response (UPR). Loss-of-function ATF6 mutations cause inherited photoreceptor diseases. Ceapin-A7 is a non-toxic, cell-permeable small molecule that selectively inhibits ATF6. We investigated how ATF6 inhibition impacts photoreceptors by treating wild-type human retinal organoids with Ceapin-A7 and evaluating the effects via single-nucleus RNA sequencing (snRNA-seq) and microscopy after 2 months. Ceapin-A7 administration effectively suppressed ATF6-dependent and UPR-related gene expression and led to fewer rod and cone inner/outer segments, malformed/stunted cone segments, and Müller gliosis, while no photoreceptor cell death was observed. When Ceapin-A7 was removed from retinal organoid media after extended exposure, photoreceptor segment quantity increased, indicating that photoreceptors were able to restore segments. These findings demonstrate that ATF6 is selectively required for photoreceptor inner/outer segment integrity. Furthermore, chemically restoring ATF6 activity promotes photoreceptor segment growth, identifying ATF6/UPR signaling as an attractive pathway to treat photoreceptor diseases.

Keywords: ATF6; Ceapin-A7; UPR; activating transcription factor 6; photoreceptor; retina; retinal organoid; unfolded protein response

DOI: https://doi.org/10.1016/j.stemcr.2026.103078

Traffic. 2026 Sep;27(3): e70054

Investigating Translocation Mechanisms of TDP-43 Into the Endoplasmic Reticulum Using Budding Yeast Models.

Miku Saito, Hana Tsuzuki, Akira Hosomi.

Signal peptides direct secretory and membrane proteins to the endoplasmic reticulum (ER), but proteins lacking classical signal peptides can occasionally engage the ER translocation machinery. TDP-43 is a nuclear RNA-binding protein implicated in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 pathology has been linked to extracellular TDP-43 species, association with the ER luminal oxidoreductase PDI, and ER stress-related phenotypes, yet whether TDP-43 fragments can directly access the ER lumen remains unclear. Here, we used budding yeast to examine signal peptide-independent ER entry of TDP-43. C-terminal fragments of TDP-43 acquired N-glycans in ste24Δ cells, whereas full-length TDP-43 showed little detectable ER entry. Endo H digestion confirmed N-glycosylation of the fragments, and a protease protection assay supported ER luminal localization of TDP-43(Δ2-89). ER entry was reduced by sec61-41 and sec66Δ, indicating engagement of a Sec61/Sec66-dependent translocation pathway. Deletion analyses identified opposing sequence elements: residues 320-343 facilitated ER entry, whereas an N-terminal region upstream of the nuclear localization signal suppressed it. TDP-43(Δ2-89) also accessed the secretory pathway, and selected disease-associated variants caused Ire1-dependent growth vulnerability without increasing detectable ER translocation. These findings reveal a Ste24-suppressed route for noncanonical ER entry of TDP-43 fragments.

Keywords: Ste24; TDP‐43; endoplasmic reticulum; signal peptide; translocon; yeast

DOI: https://doi.org/10.1111/tra.70054