bims-unfpre 2025-03-23 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–03–23
seven papers selected by
Susan Logue, University of Manitoba

Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress.
Exploring proinsulin proteostasis: insights into beta cell health and diabetes.
Pharmacological landscape of endoplasmic reticulum stress: Uncovering therapeutic avenues for metabolic diseases.
Endoplasmic Reticulum Stress in Acute Pancreatitis: Exploring the Molecular Mechanisms and Therapeutic Targets.
HaloPROTAC3 treatment activates the unfolded protein response of the endoplasmic reticulum in non-engineered mammalian cell lines.
Islet single-cell transcriptomic profiling during obesity-induced beta cell expansion in female mice.
α-synuclein expression in glioblastoma restores tumor suppressor function and rescues temozolomide drug resistance.

Mol Cells. 2025 Mar 13. pii: S1016-8478(25)00034-2. [Epub ahead of print] 100210

Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress.

Hien Thi Le, Yong Hwan Kim, Mi-Jeong Kim, Seung Hwa Hyun, Hyeeun Kim, Su Wol Chung, Yeonsoo Joe, Hun Taeg Chung, Dong-Myung Shin, Sung Hoon Back.

  eIF2α phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and NADPH homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (A/A) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven one-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of A/A cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1 (Fer-1). ATF4 overexpression suppressed impairment of GSH homeostasis in A/A cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of A/A cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.

Keywords:  ATF4; ER stress; Ferroptosis; Glutathione; Nrf2; eIF2α phosphorylation

DOI:  https://doi.org/10.1016/j.mocell.2025.100210
Front Mol Biosci. 2025 ;12 1554717

Exploring proinsulin proteostasis: insights into beta cell health and diabetes.

Parisima Ghaffarian Zavarzadeh, Kathigna Panchal, Dylan Bishop, Elizabeth Gilbert, Mahi Trivedi, Tovaria Kee, Srivastav Ranganathan, Anoop Arunagiri.

  Proinsulin misfolding is central to diabetes. This review examines the cellular mechanisms regulating proinsulin proteostasis in pancreatic β-cells, encompassing genetic factors such as insulin gene mutations, and exploring the roles of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), ER redox balance, mitochondrial function, and the influence of extrinsic factors. Mutations in the INS gene, particularly those affecting cysteine residues, impair folding and disulfide bond formation, often exhibiting dominant-negative effects on the wild-type proinsulin. The importance of ER quality control mechanisms, including chaperones and oxidoreductases, in facilitating proper folding and degradation of misfolded proinsulin is emphasized. Disruptions in these systems, due to genetic mutations, ER stress, or impaired ER-to-Golgi trafficking, lead to proinsulin accumulation and β-cell dysfunction. The unfolded protein response (UPR), especially the PERK and IRE1α-XBP1 pathways, emerges as a central regulator of protein synthesis and ER stress management. The review also discusses the role of mitochondrial health, ER redox state, and extrinsic factors such as diet and medications in influencing proinsulin proteostasis. Finally, the structural insights from NMR and molecular dynamics simulations are discussedhighlighting the dynamics of misfolding and underscoring the importance of disulfide bonds. These mechanistic insights suggest innovative strategies targeting thiol/disulfide redox systems in cells to mitigate protein misfolding diseases including diabetes.

Keywords:  beta cells; diabetes; insulin biosynthesis; proinsulin folding; proteostasis; trafficking

DOI:  https://doi.org/10.3389/fmolb.2025.1554717
Eur J Pharmacol. 2025 Mar 13. pii: S0014-2999(25)00263-8. [Epub ahead of print]998 177509

Pharmacological landscape of endoplasmic reticulum stress: Uncovering therapeutic avenues for metabolic diseases.

Ghallab Alotaibi, Abdullah Alkhammash.

  The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.

Keywords:  Endoplasmic reticulum (ER) stress; Mitochondria-ER contact sites (MERCs); Protein folding disorders; Tauroursodeoxycholic acid (TUDCA); Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.ejphar.2025.177509
Cell Stress Chaperones. 2025 Mar 17. pii: S1355-8145(25)00012-4. [Epub ahead of print]

Endoplasmic Reticulum Stress in Acute Pancreatitis: Exploring the Molecular Mechanisms and Therapeutic Targets.

Xiaoliang Zhang, Chenchen Xu, LiJuan Ji, Haiwei Zhang.

  Acute pancreatitis (AP) is associated with multiple cellular mechanisms that trigger and or are triggered by the inflammatory injury and death of the acinar cells. One of the key mechanisms is the endoplasmic reticulum (ER) stress which manifests as an accumulation of misfolded proteins within ER, an event that has pro-inflammatory and proapoptotic consequences. Hence, the degree of cell insult during AP could considerably depend on the signaling pathways that are upregulated during ER stress and its resulting dyshomeostasis such as C/EBP homologous protein (CHOP), cJUN NH2-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and NOD-like receptor protein 3 (NLRP3) inflammasome. Exploring these molecular pathways is an interesting area for translational medicine as it may lead to identifying new therapeutic targets in AP. This review of the literature aims to shed light on the different roles of ER stress in the etiopathogenesis and pathogenesis of AP. Then, it specifically focuses on the therapeutic implications of ER stress in this context.

Keywords:  CHOP; NF-κB; UPR; acute pancreatitis; endoplasmic reticulum stress; pyroptosis

DOI:  https://doi.org/10.1016/j.cstres.2025.03.001
Mol Biol Cell. 2025 Mar 19. mbcE24080342

HaloPROTAC3 treatment activates the unfolded protein response of the endoplasmic reticulum in non-engineered mammalian cell lines.

Aleksandra S Anisimova, G Elif Karagöz.

Proteins fused to HaloTag, an engineered haloalkane dehalogenase, can be depleted by a heterobifunctional degrader compound HaloPROTAC3. The binding of HaloPROTAC3 to both the HaloTag and the E3 ligase von Hippel-Lindau (VHL) brings them into proximity and mediates the degradation of the HaloTag fusion proteins. Here, we generated a colon cancer cell line HCT116 expressing HaloTag fused to the RNA-binding protein IGF2BP3 to study its function. HaloPROTAC3 treatment depleted 75% of HaloTag-IGF2BP3 in 5 hours. Transcriptomics revealed that HaloPROTAC3 treatment resulted in the destabilization of IGF2BP3 target mRNAs and activated the unfolded protein response (UPR). Surprisingly, we found that HaloPROTAC3 results in UPR activation in non-engineered mammalian cells. Our data demonstrate that HaloPROTAC3 causes mild endoplasmic reticulum stress independent of IGF2BP3 function and shall guide future studies using the HaloPROTAC3 protein depletion strategy.

DOI: https://doi.org/10.1091/mbc.E24-08-0342
iScience. 2025 Mar 21. 28(3): 112031

Islet single-cell transcriptomic profiling during obesity-induced beta cell expansion in female mice.

Peter M Masschelin, Scott A Ochsner, Sean M Hartig, Neil J McKenna, Aaron R Cox.

  Targeting beta cell proliferation is an appealing approach to restore glucose control in type 1 diabetes. However, the underlying mechanisms of beta cell proliferation remain incompletely understood, limiting identification of new therapeutic targets. Obesity is a naturally occurring process that potently induces human and rodent beta cell replication, representing an ideal model to study mechanisms of beta cell proliferation. We showed previously acute whole-body Lepr gene deletion in adult mice induces obesity and massive beta cell expansion. Here, using single-cell transcriptomics with female Lepr KO islets, we identified distinct populations of beta cells undergoing unfolded protein response (UPR), stress resolution, and cell cycle progression. Lepr KO beta cells undergoing UPR markedly increased chaperone protein, ribosomal biogenesis, and cell cycle transcriptional programs that were enriched for Xbp1 and Myc target genes. Our findings suggest a coordinated transcriptional mechanism involving Xbp1 and Myc to alleviate UPR and stimulate beta cell proliferation in obese female mice.

Keywords:  Biological sciences; Cell biology; Functional aspects of cell biology; Specialized functions of cells

DOI:  https://doi.org/10.1016/j.isci.2025.112031
Cell Death Dis. 2025 Mar 19. 16(1): 188

α-synuclein expression in glioblastoma restores tumor suppressor function and rescues temozolomide drug resistance.

Eric Duplan, Aurore Bernardin, Thomas Goiran, Nathalie Leroudier, Mathew Casimiro, Richard Pestell, Shinya Tanaka, Celine Malleval, Jerome Honnorat, Ahmed Idbaih, Lucie Martin, Hélène Castel, Frédéric Checler, Cristine Alves da Costa.

Several studies have shown that Parkinson's disease causative gene products, including α-synuclein (α-syn), display tight links with the tumor suppressor p53. The purpose of this study is to determine the implication of α-syn in glioblastoma development and elucidate how it elicits a tumor suppressor function. We show that the expression of α-syn, a TP53 transcriptional target and a key molecular player in Parkinson's disease, is detected in 1p/19q-codeleted and isocitrate dehydrogenase (IDH)-mutant oligodendroglioma and in IDH-wild-type glioblastoma, while reduced in glioblastoma biopsies, corroborating the link of α-syn expression with a better prognosis among all glioma patients. Accordingly, protein expression is drastically reduced in oligodendrogliomas and glioblastoma biopsies. This could be accounted for by a reduction of p53 transcriptional activity in these samples. Interestingly, genetic manipulation of p53 in glioblastoma cells and in mouse brain shows that p53 up-regulates α-synuclein, a phenotype fully abolished by the prominent p53 hot spot mutation R175H. Downstream to its p53-linked control, α-syn lowers cyclin D1 protein and mRNA levels and reduces glioblastoma cells proliferation in a cyclin D1-dependent-manner. Further, in temozolomide (TMZ)-resistant U87 cells, α-syn reduces O6-methylguanine-DNA methyltransferase (MGMT) expression and rescues drug sensitivity by a mechanism implying its transcriptional activation by X-box binding protein 1 (XBP1), an effector of the UPR response. Furthermore, α-syn lowers MGMT and cyclin D1 (CCDN1) expressions and reduces tumor development in allografted mice. Overall, our data reveals a new role of α-syn as an oligodendroglioma biomarker and as a glioblastoma tumor suppressor capable of either potentiate TMZ effect or avoid TMZ-associated resistance.

DOI: https://doi.org/10.1038/s41419-025-07509-z