bims-unfpre 2026-05-03 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–05–03
eight papers selected by
Susan Logue, University of Manitoba

IRE1-XBP1driven induction of TMED9 stabilizes ATF6 during ER stress to promote cell survival.
Serglycin Cooperates with the Unfolded Protein Response Pathway and Inflammation to Drive Glioblastoma Cell Survival.
The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50.
Regulation of Endoplasmic Reticulum Stress by Empagliflozin in Doxorubicin-Induced Cardiotoxicity in Rats.
Proximity Mapping of the ER Proteome Reveals Metastasis-specific Candidate Biomarkers in Breast Cancer Cell Lines.
Autophagy reshapes the aging ER.
Pi4ka downregulation triggers Creb3l2-dependent lysosomal dysfunction to promote maladaptive tubular remodeling and immune activation in acute kidney injury.
Metabolic adaptation to IMMT deficiency through the ATF6-PPARγ axis is contingent on TP53 mutation status in breast cancer.

Cell Mol Biol Lett. 2026 Apr 30.

IRE1-XBP1driven induction of TMED9 stabilizes ATF6 during ER stress to promote cell survival.

Chen Lenchisky, Areen Muhammad Majadly, Irena Bronshtein Berger, Danielle Biton, Alaa Daoud Sarsour, Narkis Arbeli, Tamar Cohen, Naama Amos, Sara Kinstlinger, Ortal Cohen, Elad Horwitz, Moran Dvela-Levitt.

   BACKGROUND: The endoplasmic reticulum (ER) plays a central role in protein homeostasis by facilitating the folding, modification, and quality control of secretory and membrane proteins. Disruption of ER function results in protein misfolding and ER stress, which activate the unfolded protein response (UPR). While the three canonical UPR branches, inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6), have been extensively studied, the mechanisms that coordinate their activities and ultimately dictate survival or death remain poorly understood. Transmembrane P24 trafficking protein 9 (TMED9), a cargo receptor that cycles between the ER and Golgi, has been implicated in protein quality control under pathological conditions, but its physiological role in ER proteostasis and UPR signaling is unclear.
METHODS: The ER stress response was studied in cellular human models including normal epithelial cells and patient-derived pediatric glioma cultures. To define the regulatory mechanisms dictating TMED9 expression, quantitative Reverse Transcription polymerase chain reaction (qRT-PCR), luciferase reporter assay, and western blotting were employed. To elucidate TMED9 function, loss-of-function approaches, including clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated knockout and small interfering RNA knockdown were used in combination with RNA-seq and live imaging. Protein stability was tested by pulse-chase experiments, ubiquitination, and degradation analyses. To study the implications of TMED9 activation, we screened curated gene expression datasets from the European Molecular Biology Laboratory- European Bioinformatics Institute (EMBL-EBI) Expression Atlas and employed live-cell imaging-based assays and functional assays (cell viability, apoptosis, migration, and self-renewal).
RESULTS: Our study uncovers a physiological role for TMED9 in ER proteostasis and UPR signaling. We show that, under ER stress, TMED9 expression is transcriptionally induced by the IRE1-spliced X-box binding protein 1 (XBP1s) pathway via a conserved unfolded protein response element (UPRE)-like element in its promoter. Removal of TMED9 selectively impairs ATF6 activation without altering IRE1 or PERK signaling, resulting in increased sensitivity to ER stress-induced apoptosis. Mechanistically, we identify TMED9 as a stress-induced stabilizer of ATF6 that prevents its ubiquitin-dependent proteasomal degradation. Functionally, TMED9 regulation is exploited by tumor cells, which sustain IRE1-XBP1s activity to upregulate TMED9, thereby enhancing survival under ER stress conditions.
CONCLUSIONS: Collectively, our findings establish TMED9 as a critical regulator of ER stress adaptation. TMED9 emerges as a molecular mediator that links IRE1-dependent transcriptional response to ATF6 stabilization, ultimately supporting increased secretory demand under stress conditions and in cancer development.

Keywords:  ATF6; DIPG; ER stress; Glioma; IRE1–XBP1s pathway; Proteostasis; TMED9; UPR; p24 proteins

DOI:  https://doi.org/10.1186/s11658-026-00931-x
Cells. 2026 Apr 09. pii: 660. [Epub ahead of print]15(8):

Serglycin Cooperates with the Unfolded Protein Response Pathway and Inflammation to Drive Glioblastoma Cell Survival.

Eleftherios N Athanasopoulos, Chrysostomi Gialeli, Angeliki Natsiou, Dimitra Manou, Vassiliki T Labropoulou, Achilleas D Theocharis.

  Serglycin (SRGN) has been found overexpressed and secreted in glioblastoma (GBM), associated with tumorigenic signaling and poor prognosis. In this study, we aimed to elucidate the involvement of SRGN in the unfolded protein response (UPR), an oncogenic signaling pathway implicated in protein recycling and cell fate. Herein, we developed stably transduced LN-18shSCR GBM cells, expressing high levels of SRGN, and SRGN-depleted LN-18shSRGN cells. We observed significantly attenuated expression and activity of all UPR mediators upon SRGN suppression, in particular PERK, IRE1, ATF6 and downstream effectors. SRGN-expressing cells possessed a constitutively active UPR, as indicated by its active phosphorylation status and accumulated pool of nuclear ATF4 in LN-18shSCR cells. Constitutive activation of the caspase-dependent apoptotic pathway was apparent in LN-18shSRGN cells. Induction of endoplasmic reticulum (ER) stress pointed out that LN-18shSRGN cells were predisposed to ER stress-associated cell death, whereas LN-18shSCR cells activated adaptive UPR signaling and displayed resistance to apoptosis. The evaluation of TLRs, TNFRs, ILs and NF-kB also underscored that SRGN is essential for their expression and active inflammatory signaling. We concluded that SRGN-expressing cells acquire a pro-survival UPR mechanism, highlighting the novel regulatory role of SRGN in the adaptation and survival of GBM cells.

Keywords:  apoptosis; extracellular matrix; glioblastoma; inflammation; proteoglycans; serglycin; unfolded protein response

DOI:  https://doi.org/10.3390/cells15080660
Nat Commun. 2026 Apr 27.

The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50.

Admire Munanairi, David A Rudnick, Jiansheng Huang, David H Perlmutter.

In previous studies we have shown that accumulation of the polymerogenic variant ATZ that causes α1-antitrypsin deficiency (ATD) activates NFκB DNA binding. Here we discovered that this response, which we are naming the polymerized protein response (PPR), is characterized by NFκB p50 homodimers, distinct from the p50/p65 heterodimers in the canonical NFκB inflammatory response and the unfolded protein response (UPR). The PPR is also activated by other disease associated variants that polymerize in the ER whereas disease-associated variants that do not form polymers activate p50/p65 heterodimers and UPR. The PPR elicits a unique gene expression profile, including changes that stabilize p50 homodimers in cytoplasm and nucleus. The PPR is blocked by specific genetic substitutions within the luminal and cytosolic domains of Derlin-2 providing evidence that the ERAD retrotranslocation complex is a proximal transducer of this signaling mechanism. We hypothesize that the PPR is a proteostasis response pathway complementary to the UPR, designed to protect the cell from the specific proteotoxic effects of polymers that form aberrantly in the ER.

DOI: https://doi.org/10.1038/s41467-026-72369-w
J Cell Mol Med. 2026 May;30(9): e71161

Regulation of Endoplasmic Reticulum Stress by Empagliflozin in Doxorubicin-Induced Cardiotoxicity in Rats.

Akshi Malik, David C Y Cheung, D Allison Ledingham, Danielle Desautels, Joerg Herrmann, Pawan K Singal, Davinder S Jassal.

  Although Doxorubicin (Dox) is an effective anticancer drug, it can cause severe cardiotoxicity. While several mechanisms have been proposed to explain Dox-induced cardiomyopathy (DIC), strategies to prevent it remain limited. In previous research on isolated cardiomyocytes, we identified that Empagliflozin (EMPA), an antidiabetic drug, mitigated Dox-induced ER stress and apoptosis. In this in vivo study using rats, we further investigated EMPA's potential in preventing and treating DIC. Rats administered a cumulative dose of 15 mg/kg Dox exhibited significant cardiovascular damage, including left ventricular cavity dilation, decreased left ventricular ejection fraction (LVEF), ER dilation, mitochondrial defects and vacuole formation. These structural changes were linked to the activation of ER-stress pathways (PERK, IRE1 and ATF6) and upregulation of apoptotic proteins initiated by ER stress. When EMPA (10 mg/kg/day) was administered either prophylactically or concurrently with Dox, it significantly attenuated adverse LV remodelling and preserved LVEF. Additionally, EMPA prevented ER stress and subsequent apoptosis in the myocardium of the Dox + EMPA-treated group. These findings suggest that EMPA offers cardioprotective benefits in DIC, likely through the inhibition of ER-stress-induced myocardial injury.

Keywords:  Empagliflozin; apoptosis; doxorubicin‐induced cardiomyopathy; endoplasmic‐reticulum stress

DOI:  https://doi.org/10.1111/jcmm.71161
Cancer Genomics Proteomics. 2026 May-Jun;23(3):23(3): 483-502

Proximity Mapping of the ER Proteome Reveals Metastasis-specific Candidate Biomarkers in Breast Cancer Cell Lines.

Mehmet Sarihan, Elifcan Kocyigit, Murat Kasap, Gurler Akpinar.

   BACKGROUND/AIM: Breast cancer is the most frequently diagnosed cancer among women. While biomarkers are critical for early detection and therapy, current markers lack sufficient specificity and sensitivity. The endoplasmic reticulum (ER) plays a central role in protein folding, post-translational modification, and lipid metabolism, and its alterations are linked to tumor progression. This study aimed to map ER proteome changes associated with breast cancer invasiveness and identify novel candidate biomarkers.
MATERIALS AND METHODS: We compared the ER proteomes of non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cell lines using an ER-targeted TurboID proximity labelling approach, followed by LC-MS/MS analysis. Bioinformatic analyses were performed to determine functional associations and differential expression related to invasion and metastasis for the candidate biomarkers.
RESULTS: A total of 2,079 proteins were identified, including 1,378 ER proteins. Analysis revealed that more than four hundred ER-resident or associated proteins were differentially regulated in invasive MDA-MB-231, many of which were linked to invasion and metastasis. Upregulated proteins were involved in cellular localization, ECM remodeling, cell mobility, adhesion, vesicle trafficking, and ER stress, whereas downregulated proteins were primarily associated with energy metabolism. Additionally, in this study, 36 ER-associated proteins were identified for the first time as candidates linked to breast cancer, highlighting their potential as novel biomarkers and therapeutic targets.
CONCLUSION: ER-targeted TurboID proximity labelling effectively maps the proteomic landscape of breast cancer cells, revealing functional adaptations that support invasive and metastatic phenotypes. Notably, 36 ER proteins were identified as novel candidates not previously linked to breast cancer, highlighting new potential biomarkers and therapeutic targets. These findings provide valuable insights into ER proteome remodeling, offering avenues for understanding breast cancer progression and strategies to prevent metastasis.

Keywords:  Breast cancer; ER-proteome; biomarker; biotinylation; invasion and metastasis

DOI:  https://doi.org/10.21873/cgp.20586
Autophagy. 2026 Apr 27. 1-2

Autophagy reshapes the aging ER.

Eric K F Donahue, Kristopher Burkewitz.

  Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum (ER) that is actively driven by ER-phagy. Across multiple cell types and organisms, the ER undergoes a reduction in volume and a shift from rough ER sheets to tubular networks. ER compositional shifts accompany these changes in morphology, with declines of the proteostasis machineries enriched within rough ER and preservation of lipid-associated enzymes tied to tubular subdomains. This remodeling occurs via autolysosomal targeting and degradation of the ER, establishing selective ER-phagy as a conserved aspect of the aging process. Notably, ER-phagy is also engaged by multiple longevity paradigms, resulting in precocious, spatial reorganization of the ER. Furthermore, ER-phagy is required for lifespan extension during mTOR impairment, indicating that ER turnover is adaptive and contributes to longevity. These findings reveal ER-phagy as a regulator of organelle architecture and age-dependent shifts in cell metabolism, thus illuminating important roles for selective autophagy in shaping organelle identity and function across the lifespan.Abbreviations: ER: endoplasmic reticulum; TMEM-131: transmembrane protein 131; UPR: unfolded protein response; IRE-1: inositol-requiring enzyme 1; XBP-1: X-box binding protein 1; mTOR: mechanistic target of rapamycin.

Keywords:  ER-phagy; Endoplasmic reticulum; mTOR; protein homeostasis; unfolded protein response

DOI:  https://doi.org/10.1080/15548627.2026.2662429
Cell Death Dis. 2026 Apr 27.

Pi4ka downregulation triggers Creb3l2-dependent lysosomal dysfunction to promote maladaptive tubular remodeling and immune activation in acute kidney injury.

Zhimin Chen, Jingzhi Xie, Chengkun Wu, Keng Ye, Yue Chen, Yankun Song, Huabin Ma, Jianfeng Wu, Li Chen, Yanfang Xu.

Acute kidney injury (AKI) is driven by maladaptive tubular responses, yet upstream regulators remain incompletely understood. Here, we identify phosphatidylinositol 4-kinase alpha (Pi4ka) as a critical determinant of proximal tubule cell (PTC) homeostasis and injury progression. PI4KA expression was reduced in human diseased kidneys and negatively correlated with renal function. Single-cell RNA sequencing in mouse models revealed that Pi4ka deficiency preferentially perturbs specific PTC states, including Slc34a1+Ccn1+, and Slc34a1+Apob+ populations, which diverge along distinct maladaptive trajectories. From these trajectories we derived a 40-gene injury signature enriched for lysosome-associated pathways, and functional assays showed that lysosomal dysfunction is an early event linking Pi4ka loss to ER stress, impaired autophagy, and proteostasis disruption. Transcriptional network analysis identified Creb3l2 as a central regulator of lysosomal activation. Notably, Creb3l2 perturbation suppressed stress and cell-death programs while promoting transcriptional programs associated with repair and phospholipid metabolism. Ligand-receptor inference further indicated that Pi4ka-deficient PTCs shape a pro-inflammatory immune microenvironment via immunomodulatory gene activation, an effect abolished by Creb3l2 deletion. Collectively, these findings define a Pi4ka-lysosome-Creb3l2 axis that coordinates tubular injury, maladaptive remodeling, and immune activation, highlighting potential therapeutic targets to limit AKI progression.

DOI: https://doi.org/10.1038/s41419-026-08794-y
Cell Death Dis. 2026 Apr 28.

Metabolic adaptation to IMMT deficiency through the ATF6-PPARγ axis is contingent on TP53 mutation status in breast cancer.

Li Liu, Dan Li, Zeyu Hou, Yi Huang, Jinjing Wang, Chaorui Pu, Qingqing Zhao, Yunyan Yu, Rui Chen.

Mitochondrial dysfunction and the corresponding metabolic reprogramming have been established as critical drivers of tumor progression; nevertheless, the specific molecular mechanisms have not yet been fully elucidated. In this study, we reveal that ablation of inner mitochondrial membrane protein (IMMT), a key architectural component of mitochondrial cristae, induces concurrent mitochondrial and endoplasmic reticulum stress (ERS), which selectively activates the ATF6-mediated unfolded protein response (UPR) to drive breast cancer (BC) cell proliferation. Mechanistically, IMMT loss promotes ATF6α-ATF6β heterodimer formation, whereby ATF6α stabilizes ATF6β protein, enabling ATF6β to engage PPARγ through direct physical interaction and orchestrate redox homeostasis remodeling that sustains tumor cell proliferation. Notably, we discovered that this compensatory stress adaptation is context-dependent, manifesting specifically in TP53-mutant tumors, but not in their wild-type counterparts, and targeted disruption of the ATF6β-PPARγ signaling axis effectively abrogates the oncogenic effects induced by IMMT-KO. Our work uncovers a previously unrecognized adaptive axis linking chronic mitochondrial dysfunction to redox control in BC and establishes ATF6β as a critical effector that partners with PPARγ under stress-a functional role distinct from its classical regulatory relationship with ATF6α. These findings provide a theoretical foundation for precision therapeutic strategies targeting vulnerabilities in the stress adaptation pathway of BC.

DOI: https://doi.org/10.1038/s41419-026-08813-y