bims-unfpre 2026-09-06 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–09–06
six papers selected by
Susan Logue, University of Manitoba

QRICH1 Suppresses Glioma Progression by Inducing ER Stress and Activating the PERK-ATF4-CHOP Pathway.
Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
The moonlighting functions of SEC13 in nonsense-mediated mRNA decay and the regulation of ER stress.
Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.
Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.
p38β-mediated BiP phosphorylation drives stemness and chemoresistance by suppressing UPR activation in hepatocellular carcinoma.

Cancer Med. 2026 Sep;15(9): e72217

QRICH1 Suppresses Glioma Progression by Inducing ER Stress and Activating the PERK-ATF4-CHOP Pathway.

Yunjiang Wang, Min Xu, Zhenglou Chen, Xuqi Huo, Ya Xue, Xiang Ji, Yang Shen, Hongsheng Wang.

   BACKGROUND: ER stress (ERS) influences tumor behavior through the unfolded protein response (UPR), yet its role in glioma is not fully defined. This study investigated the function of the ERS-related regulator QRICH1 in glioma progression.
METHODS: Public databases (TCGA and GTEx) were used to evaluate QRICH1 expression, survival, and prognostic significance in glioma. Lentiviral QRICH1 overexpression or knockdown was established in U87 and U251 cells, followed by functional and mechanistic assays. A subcutaneous xenograft model, histological analyses, and immunohistochemistry were performed to validate the biological function of QRICH1 in vivo.
RESULTS: QRICH1 was markedly upregulated in glioma and associated with better patient survival. QRICH1 overexpression suppressed glioma proliferation, migration, and invasion while promoting apoptosis, whereas silencing QRICH1 enhanced malignancy. Mechanistically, QRICH1 activated the PERK-ATF4-CHOP pathway, increased caspase-12 cleavage, and strengthened ERS-induced apoptosis. In vivo, QRICH1 overexpression reduced tumor size and increased apoptotic markers.
CONCLUSION: QRICH1 shifts QRICH1 shifts the UPR toward its pro-apoptotic branch, thereby inhibiting glioma progression, and represents a promising prognostic biomarker and therapeutic target.

Keywords:  QRICH1; bioinformatics; endoplasmic reticulum stress; unfolded protein‐response

DOI:  https://doi.org/10.1002/cam4.72217
Pharmacol Res. 2026 Aug 31. pii: S1043-6618(26)00343-9. [Epub ahead of print]232 108428

Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.

Ester Zito, György Hajnóczky.

  Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease pathogenesis. Here, we examine the molecular mechanisms that govern adaptive and maladaptive UPR signaling and discuss how these ER-centered responses impinge on mitochondrial and cellular physiology. We analyze three major drivers of coupling mitochondrial function to UPR signaling: (i) enhanced ERMCs, (ii) IP3R-mediated Ca²⁺ transfer from the ER to mitochondria, and (iii) bidirectional ROS/H₂O₂ exchange between the two organelles. We also discuss unresolved questions in the field and technological advances, including approaches to investigate ERO1-dependent redox nanodomains, ERO1 inhibitors and engineered ERMC linkers, that are advancing our understanding of ER-mitochondria crosstalk and revealing potential therapeutic opportunities. These insights may inform precision medicine strategies for diseases driven by chronic ER stress and mitochondrial dysfunction.

Keywords:  CHOP; Ca²⁺ handling; ER stress; ERO1; ER–mitochondria contact sites (ERMCs); IP₃ receptor (IP₃R); Mitochondrial permeability transition pore (mPTP); Pharmacological therapy; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.phrs.2026.108428
RNA. 2026 Sep 02. pii: rna.081099.126. [Epub ahead of print]

The moonlighting functions of SEC13 in nonsense-mediated mRNA decay and the regulation of ER stress.

Laura Monaghan, Chetan Srinath, Abigail R Mann, Nila Roy Choudhury, Graeme R Grimes, Dasa Longman, Javier F Caceres.

  The nonsense-mediated decay pathway (NMD) is an RNA quality control mechanism that regulates the stability of target RNAs. We previously identified the ER-localized SEC13 protein as a novel NMD factor in C. elegans and in HeLa cells; raising the possibility that it could be involved in regulating the stability of mRNAs translated at the ER. SEC13 is a component of several cellular complexes, including the COPII vesicle coat, the nuclear pore complex (NPC) and the nutrient sensing GATOR2 complex. Here, we show that SEC13 interacts with core NMD factors and using a newly developed dual-color fluorescent NMD sensor in U2OS cells, we assessed SEC13 NMD activity, at a single-cell level. Transcriptomic profiling revealed that unlike the previously described ER-NMD factor, NBAS, SEC13 co-regulates the stability of substrates translated both in the cytoplasm and at the ER. We also show that SEC13 function in NMD is largely independent of its function in other cellular complexes. Altogether, these results show that SEC13 is a bona fide NMD factor in mammalian cells. Finally, we utilized an ER stress-activated indicator (ERAI) in U2OS cells to demonstrate that SEC13, together with canonical NMD factors, has a role in the regulation of the unfolded protein response (UPR) at the ER. Thus, the moonlighting functions of SEC13 include a role in NMD pathway and the regulation of ER stress.

Keywords:  Moonlighting; RNA-quality control; SEC13; Stress response; nonsense-mediated decay (NMD)

DOI:  https://doi.org/10.1261/rna.081099.126
Cell Death Dis. 2026 Aug 07. pii: 766. [Epub ahead of print]17(1):

Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.

Na Li, Yanhong Ding, Bowen Yu, Yongqiang Wang, Tongbin Gao, Huiyong Yin, Zhenhua Li, Shuzhen Liu, Guohua Yu, Ningning Wang.

Clear cell renal cell carcinoma (ccRCC) exhibits a paradoxical fructose metabolism signature characterized by upregulation of the fructose transporter GLUT5 alongside downregulation of the catabolic enzymes (ketohexokinase, aldolase B, and triokinase), a pattern associated with poor prognosis. Functionally, unlike the pro-survival effect of fructose under glucose deprivation, in the presence of glucose, fructose co-treatment suppresses ccRCC cell proliferation, and induces profound mitochondrial dysfunction, including impaired oxidative phosphorylation, loss of membrane potential, excessive mitochondrial superoxide production, reduced mtDNA copy number, and downregulation of mitochondria-encoded electron transport chain subunits (notably ND2 and ND4 of complex I). Mechanistically, co-treatment with glucose and fructose creates a metabolic trap resulting in fructose-1-phosphate accumulation and ATP depletion. This energy crisis drives profound depletion of purine and pyrimidine nucleotide pools, which selectively triggers the PERK-eIF2S1-ATF4-CHOP axis of the integrated stress response, thereby mediating mitochondrial impairment and ultimately sensitizing ccRCC cells to intrinsic apoptosis via BID cleavage and caspase-3 activation under nutrient stress. Pharmacological treatment with the chemical chaperone 4-phenylbutyric acid (4-PBA) or nucleoside supplementation reverses mitochondrial dysfunction and fructose-induced cytotoxicity. The tumor-suppressive effect of fructose is validated in patient-derived organoids and xenograft mouse models, where fructose administration significantly attenuates tumor growth via ER stress. These findings reveal fructose-driven nucleotide depletion and PERK-dependent ER stress leading to mitochondrial dysfunction, which underlies the tumor-suppressive toxicity of fructose and exposes a targetable metabolic vulnerability in ccRCC.

DOI: https://doi.org/10.1038/s41419-026-09157-3
Blood Adv. 2026 Sep 04. pii: bloodadvances.2026019895. [Epub ahead of print]

Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.

Hyunjoo Choi, Sang-Eun Jung, Yesenia Earth, Hyojung Paik, Shuyang Lin, Jiye Yi, Maggie J Cox, Stephen M Sykes, Stephen T Oh, Yoon-A Kang.

Unfolded protein response (UPR) promotes protein homeostasis under endoplasmic reticulum stress. UPR signaling has numerous functions in metabolism, cancer, immunology, and neurodegenerative diseases. Recent studies also showed that UPR signaling has important roles in hematopoietic stem and progenitor cell biology. However, whether UPR signaling regulates hematopoietic lineage fate decision remains elusive. Here, we found that FcgR- MPP3 generates erythroid lineage and Jak2V617F mutation leads to overproduction of erythroid cells by expanding FcgR- MPP3. We showed that UPR signaling increases myeloid cell production through promoting FcgR- MPP3 transition to granulocyte/macrophage progenitor producing FcgR+ MPP3 at the expense of erythroid lineage via the XBP1 pathway. Under a disease condition, UPR signaling cooperates with Jak2V617F mutation and exacerbates disease phenotype in a mouse model of polycythemia vera (PV) through the ATF4 pathway. Activation of UPR signaling also increased myeloid output in healthy donor bone marrow MPP cells while skewing the output towards erythroid lineage in PV patient bone marrow MPP cells. Together, our results identify a novel function of UPR signaling in hematopoietic lineage specification and provide critical insights into targeting UPR signaling in hematological malignancies.

DOI: https://doi.org/10.1182/bloodadvances.2026019895
Nat Commun. 2026 Aug 05. pii: 9415. [Epub ahead of print]17(1):

p38β-mediated BiP phosphorylation drives stemness and chemoresistance by suppressing UPR activation in hepatocellular carcinoma.

Liang Xu, Ianto Bosheng Huang, Minghe Zhang, Yunong Xie, Bing Li, Linglin Liu, Long Hin Ng, Yimiao He, Yan Liu, Tin-Lok Wong, Xiaoyun Lu, Terence Kin-Wah Lee, Jing-Ping Yun, Lei Jin, Stephanie Ma, Man Tong.

Tumor-initiating cells (TICs) promote tumor initiation and therapy resistance, yet the kinase regulators that sustain TICs remain incompletely defined. Here, we identify the stress kinase p38β (MAPK11) supports TIC maintenance and drug resistance in hepatocellular carcinoma (HCC). Integrated analysis of chemotherapy-enriched HCC spheroids, and DepMap data prioritized p38β as a kinase linked to stemness and chemoresistance. High p38β expression correlates with poor prognosis and aggressive clinicopathological features in HCC patients. Mechanistically, p38β phosphorylates the endoplasmic reticulum (ER) chaperone BiP at threonine 648, enhancing its association with the unfolded protein response (UPR) sensors PERK and IRE1-α. This modification suppresses UPR activation and reduces unfolded protein accumulation, thereby preserving ER proteostasis under chemotherapeutic stress. Functionally, p38β-driven BiP phosphorylation sustains TIC phenotypes and cisplatin resistance in vitro and in vivo. BiP inhibition with HA15 restores UPR signaling and sensitizes patient-derived xenograft and organoid models to cisplatin, revealing a targetable p38β-BiP axis in HCC.

DOI: https://doi.org/10.1038/s41467-026-76073-7