bims-unfpre 2025-05-11 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–05–11
eight papers selected by
Susan Logue, University of Manitoba

USP18 attenuates endoplasmic reticulum stress via the PERK-eIF2α-ATF4 axis to reduce apoptosis in hepatocellular carcinoma cells.
Cigarette smoke induces endoplasmic reticulum stress-associated mucus hypersecretion via orosomucoid 1-like protein 3 in airway epithelia.
Reprograming gene expression in 'hibernating' C. elegans involves the IRE-1/XBP-1 pathway.
Unveiling the intercompartmental signaling axis: Mitochondrial to ER Stress Response (MERSR) and its impact on proteostasis.
Editorial Expression of Concern: Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress.
Paraoxonase-like APMAP maintains endoplasmic-reticulum-associated lipid and lipoprotein homeostasis.
Reticulon-dependent ER-phagy mediates adaptation to heat stress in C. elegans.
Effects of Ire1 gene on virulence and pathogenicity of Candida albicans.

Sci Rep. 2025 May 05. 15(1): 15659

USP18 attenuates endoplasmic reticulum stress via the PERK-eIF2α-ATF4 axis to reduce apoptosis in hepatocellular carcinoma cells.

Lin Li, Nana Liu, Pujuan Yang, Chunyan Rao, Lingna Kong, Yi Huang, Qingsong Lei, Huabao Liu.

  Ubiquitin-specific peptidase 18 (USP18) is a specific interferon-stimulated gene 15 demodifying enzyme that plays an important role in apoptosis. In this study, we investigated the role of USP18 in apoptosis in hepatocellular carcinoma cells, especially its ability to regulate apoptosis through endoplasmic reticulum (ER) stress. We found that protein levels of Bcl-2-associated protein x and cytochrome c were down-regulated by USP18, which suppressed the classical mitochondrial-mediated apoptosis pathway. USP18 also inhibited apoptosis through the unfolded protein response (UPR) pathway by inhibiting the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and the expression of CCAAT/enhance-binding protein homologous protein, which is a downstream marker molecule of ER stress. The UPR triggered by ER stress eventually led to the cleavage of downstream effecter proteases, including caspase-3, leading to apoptosis. Furthermore, USP18 combined with a PERK agonist regulated apoptosis through the PERK-eukaryotic initiation factor-2α-activating transcription factor 4 axis of the UPR. Our results show that USP18 participates in the regulation of hepatocellular carcinoma cell apoptosis through different pathways, especially the ER stress pathway, and that it plays a complex role in cell stress responses and apoptosis regulation.

Keywords:  Apoptosis; Endoplasmic reticulum stress; Hepatocellular carcinoma; Protein kinase RNA-like Endoplasmic reticulum kinase; Ubiquitin-specific peptidase 18

DOI:  https://doi.org/10.1038/s41598-025-00540-2
Free Radic Res. 2025 May 08. 1-14

Cigarette smoke induces endoplasmic reticulum stress-associated mucus hypersecretion via orosomucoid 1-like protein 3 in airway epithelia.

Rui Chen, Yuting Cui, Mary Sau-Man Ip, Judith Choi-Wo Mak.

  Apart from a strong association with childhood-onset asthma, orosomucoid 1-like protein 3 (ORMDL3), an endoplasmic reticulum (ER)-localized transmembrane protein, is also linked with chronic obstructive pulmonary disease (COPD), in which cigarette smoke (CS) is the crucial risk factor. Compared to healthy subjects, COPD patients had elevated ORMDL3 mRNA in well-differentiated primary human bronchial epithelial cells (HBECs). However, its role in COPD remains understudied. We, therefore, hypothesize that ORMDL3 may play an essential role in CS-induced chronic mucus hypersecretion and inflammation via activation of specific unfolded protein response (UPR) pathways under ER stress in primary HBECs. Gene silencing using siRNA for ORMDL3 was performed in submerged culture of primary HBECs before 24-h cigarette smoke medium (CSM) exposure. The mucin, inflammatory and mitochondrial markers, and the activation of the UPR pathways were evaluated. CSM triggered significant induction of ORMDL3 expression at both mRNA and protein level, which was significantly inhibited by silencing ORMDL3. In addition, ORMDL3 knockdown inhibited CSM-induced mucin MUC5AC mRNA and release of inflammatory marker interleukin (IL)-8. Silencing ORMDL3 reduced CSM-induced ER stress via inhibiting the activating transcription factor (ATF)6 and the inositol-requiring enzyme (IRE)1 of the UPR pathways. The involvement of ORMDL3 was demonstrated in mitochondrial dynamics via fusion protein Mfn2 and mitochondrial respiration after CSM stimulation. In conclusion, ORMDL3 is an inducible gene in mediating CS-induced activation of specific ATF6 and IRE1 pathways to regulate mucus hypersecretion and inflammation. Therefore, ORMDL3 may be a promising therapeutic target to treat smoking-associated mucus hypersecretion and inflammation in COPD.

Keywords:  COPD; ORMDL3; cigarette smoke; mucus hypersecretion; unfolded protein response

DOI:  https://doi.org/10.1080/10715762.2025.2501019
Elife. 2025 May 06. pii: RP101186. [Epub ahead of print]13

Reprograming gene expression in 'hibernating' C. elegans involves the IRE-1/XBP-1 pathway.

Melanie Lianne Engelfriet, Yanwu Guo, Andreas Arnold, Eivind Valen, Rafal Ciosk.

  In nature, many animals respond to cold by entering hibernation, while in clinical settings, controlled cooling is used in transplantation and emergency medicine. However, the molecular mechanisms that enable cells to survive severe cold are still not fully understood. One key aspect of cold adaptation is the global downregulation of protein synthesis. Studying it in the nematode Caenorhabditis elegans, we find that the translation of most mRNAs continues in the cold, albeit at a slower rate, and propose that cold-specific gene expression is regulated primarily at the transcription level. Supporting this idea, we found that the transcription of certain cold-induced genes is linked to the activation of unfolded protein response (UPR) through the conserved IRE-1/XBP-1 signaling pathway. Our findings suggest that this pathway is triggered by cold-induced perturbations in proteins and lipids within the endoplasmic reticulum, and that its activation is beneficial for cold survival.

Keywords:  C. elegans; ER stress; UPR; cell biology; cold dormancy; global translation; hibernation; hypothermia

DOI:  https://doi.org/10.7554/eLife.101186
PLoS Genet. 2025 May 08. 21(5): e1011700

Unveiling the intercompartmental signaling axis: Mitochondrial to ER Stress Response (MERSR) and its impact on proteostasis.

Jeson J Li, Nan Xin, Chunxia Yang, Bo G Kim, Larissa A Tavizon, Ruth Hong, Jina Park, Travis I Moore, Rebecca George Tharyan, Adam Antebi, Hyun-Eui Kim.

Maintaining protein homeostasis is essential for cellular health. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response, activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPRER), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPRER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2α signaling pathway, increasing phosphorylation of eIF2α and improving the ER's ability to handle proteostasis. MERSR activation in both polyglutamine and amyloid-beta peptide-expressing C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provide further evidence for the importance of intercompartmental signaling.

DOI: https://doi.org/10.1371/journal.pgen.1011700
Oncogene. 2025 May 08.

Editorial Expression of Concern: Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress.

L Dong, C C Jiang, R F Thorne, A Croft, F Yang, H Liu, C E de Bock, P Hersey, X D Zhang.

DOI: https://doi.org/10.1038/s41388-025-03436-7
Dev Cell. 2025 Apr 27. pii: S1534-5807(25)00210-2. [Epub ahead of print]

Paraoxonase-like APMAP maintains endoplasmic-reticulum-associated lipid and lipoprotein homeostasis.

Blessy Paul, Holly Merta, Rupali Ugrankar-Banerjee, Monica R Hensley, Son Tran, Goncalo Dias do Vale, Lauren Zacherias, Charles K Hewett, Jeffrey G McDonald, Joan Font-Burgada, Thomas P Mathews, Steven A Farber, W Mike Henne.

  Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored when compared with mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuring Drosophila, zebrafish, and mammalian hepatocytes, here we characterize the paraoxonase-like C20orf3/adipocyte plasma-membrane-associated protein (APMAP) as an ER-localized antioxidant that suppresses ER lipid oxidation to safeguard ER function. APMAP-depleted cells exhibit defective ER morphology, ER stress, and lipid peroxidation dependent on ER-oxidoreductase 1α (ERO1A), as well as sensitivity to ferroptosis and defects in ApoB-lipoprotein homeostasis. Similarly, organismal APMAP depletion in Drosophila and zebrafish perturbs ApoB-lipoprotein homeostasis. Strikingly, APMAP loss is rescued with chemical antioxidant N-acetyl-cysteine (NAC). Lipidomics identifies that APMAP loss elevates phospholipid peroxidation and boosts ceramides-signatures of lipid stress. Collectively, we propose that APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis in the ER network.

Keywords:  ER; PON; ceramide; endoplasmic reticulum; lipoprotein; paraoxonase; redox homeostasis

DOI:  https://doi.org/10.1016/j.devcel.2025.04.008
Curr Biol. 2025 May 02. pii: S0960-9822(25)00457-9. [Epub ahead of print]

Reticulon-dependent ER-phagy mediates adaptation to heat stress in C. elegans.

Claudia Serot, Vincent Scarcelli, Alexandre Pouget, Céline Largeau, Audrey Sagot, Kenza El-Hachami, Denis Dupuy, Emmanuel Culetto, Christophe Lefebvre, Renaud Legouis.

  The selective degradation of endoplasmic reticulum (ER) by autophagy, named ER-phagy, promotes the recovery of ER homeostasis after stress. Depending on the ER stress, different types of ER-phagy involve various selective autophagy receptors. In this study, we report a macroER-phagy induced by the fragmentation of tubular ER in response to acute heat stress. We identified a novel ER-phagy receptor encoded by the reticulon long isoform RET-1d. RET-1d is mainly expressed in the nervous system and the epidermis and colocalizes with the ubiquitin-like autophagy protein LGG-1/GABARAP during heat-stress-induced autophagy. Two LC3-interacting region (LIR) motifs in the long intrinsically disordered region of RET-1d mediate its interaction with the LGG-1 protein. The specific depletion of the RET-1d isoform or the mutations of the LIRs resulted in a defective ER-phagy and a decrease in the capacity of animals to adapt to heat stress. Our data revealed a RET-1d- and LGG-1-dependent ER-phagy mechanism that takes place in neurons and epidermis and participates in the adaptation of C. elegans to heat stress.

Keywords:  ER stress; LGG-1/Gabarap; LIR motif; RET-1 isoforms; autophagosomes; autophagy; development; endoplasmic reticulum; locomotion; neuron

DOI:  https://doi.org/10.1016/j.cub.2025.04.028
Open Life Sci. 2025 ;20(1): 20221062

Effects of Ire1 gene on virulence and pathogenicity of Candida albicans.

Huihai Zhao, Lixia Qin, Mengyan Li, Mengyu Jiang, Mengge Cui, Hua Wang, Baohua Hou, Fukun Wang, Keran Jia.

  With the extensive utilization of antifungal drugs, the drug resistance of Candida albicans is progressively intensifying, and the effect of empirical treatment for C. albicans infection is not evident. There is an urgent need for novel strategies and methods for the treatment of C. albicans infection. Our study utilized the previously constructed C. albicans Ire1 double gene deletion strain to explore the influence of the Ire1 on endoplasmic reticulum (ER) stress and pathogenicity of C. albicans through drug stress phenotype testing, biofilm and hyphomycete formation testing, and mouse systemic infection testing. The results indicate that Ire1 is involved in maintaining the integrity of the C. albicans cell wall and influencing the hyphal formation ability of C. albicans. Concurrently, the deletion of the Ire1 increased the sensitivity of C. albicans to the ER stress agents tunicamycin and dithiothreitol and diminished the biofilm formation ability of C. albicans in vitro, resulting in significant inhibition of the growth of C. albicans. In mouse models, the deletion of Ire1 completely nullified the virulence and pathogenicity of C. albicans in the tail vein infection. In conclusion, Ire1 might be a key target for the potential development of new therapeutic drugs and vaccines.

Keywords:  Candida albicans; Ire1; endoplasmic reticulum; virulence

DOI:  https://doi.org/10.1515/biol-2022-1062