bims-unfpre 2026-04-19 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–04–19
six papers selected by
Susan Logue, University of Manitoba

Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.
Metabolite import by SLC33A1 is required for ATF6 activation during endoplasmic reticulum stress.
Wntless degradation mediated by CaMKII inhibition drives endoplasmic reticulum stress and apoptosis.
Sucralose inhibited cell survival through the activation of ER stress in human endothelial progenitor cells.
Endoplasmic reticulum stress and the unfolded protein response in lung diseases: molecular pathways and therapeutic interventions.
SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.

Signal Transduct Target Ther. 2026 Apr 16. pii: 136. [Epub ahead of print]11(1):

Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.

Siyu Wei, Nan Zhang, Hao Zhang, Zigui Chen, Shuyu Li, Wantao Wu, Zaoqu Liu, Zhiwei Xia, Peng Luo, Quan Cheng.

Endoplasmic reticulum (ER) stress is a key cellular mechanism that is important in the development of many diseases, including cancer. Since the discovery of the unfolded protein response (UPR), research has greatly improved our understanding of how ER stress affects cellular functions, especially protein folding and adaptation to stress. The UPR consists of three main branches: IRE1, ATF6, and PERK, each of which is crucial for regulating stress responses, protein homeostasis, and apoptosis. These pathways normally help cells handle stress effectively; however, excessive or prolonged activation can lead to cell death and disease progression. In cancer, ER stress not only shapes the tumor environment but also supports immune evasion, making treatment more challenging. Moreover, ER stress is linked to a wide range of other diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic issues, and autoimmune diseases. ER stress can cause inflammation, protein buildup, and disrupted immune responses in these cases. Targeting the pathways involved in ER stress is a promising therapeutic approach with the potential to reduce disease severity and improve treatment outcomes by restoring cellular balance. The current review systematically integrates current findings on the signaling pathways and regulatory mechanisms of ER stress, examines its role in a wide range of diseases, and explores potential therapeutic strategies aimed at modulating this response. By focusing on the complex relationship between ER stress and different diseases, this investigation aims to guide future research and clinical efforts targeting ER stress-related pathways.

DOI: https://doi.org/10.1038/s41392-026-02600-z
Life Sci Alliance. 2026 Jun;pii: e202603679. [Epub ahead of print]9(6):

Metabolite import by SLC33A1 is required for ATF6 activation during endoplasmic reticulum stress.

Ginto George, Heather P Harding, Richard Kay, David Ron, Adriana Ordoñez.

The transcription factor ATF6α has a central role in adapting mammalian cells to ER stress via the unfolded protein response (UPR), prompting efforts to identify ATF6α modulators. Here, an unbiased genome-wide CRISPR-Cas9 screen performed in Chinese Hamster Ovary cells revealed that proteolytic processing of the ATF6α precursor to its active form was impaired in cells lacking the ER-resident solute carrier SLC33A1, a transporter previously implicated in acetyl-CoA import, sialylation, and Nε-lysine protein acetylation. Cells lacking SLC33A1 constitutively trafficked the ATF6α to the Golgi but exhibited impaired Golgi processing and activating proteolysis. IRE1α signalling was derepressed by SLC33A1 deficiency consistent with selective loss of ATF6α-mediated negative feedback in the UPR. Slc33a1-deleted cells accumulated unmodified sialylated N-glycans, precursors to acetylated glycans, likely reflecting impaired glycan processing. Deletion of ER-localised acetyltransferases NAT8 and NAT8B, which catalyse protein Nε-lysine acetylation in the secretory pathway, did not replicate the ATF6α processing defects observed in Slc33a1-deficient cells. Together, our findings highlight a role of SLC33A1-mediated metabolite transport in the post-ER ATF6α maturation, linking small-molecule metabolism to branch-specific signalling in the UPR.

DOI: https://doi.org/10.26508/lsa.202603679
Cell Rep. 2026 Apr 11. pii: S2211-1247(26)00334-7. [Epub ahead of print]45(4): 117256

Wntless degradation mediated by CaMKII inhibition drives endoplasmic reticulum stress and apoptosis.

Zhongkai Gu, Jude Owiredu, Betul Ersoy-Fazlioglu, Bailin Wu, Michael Lu, Steven P Balk, Xin Yuan.

  Noncanonical Wnt signaling stimulates calcium release and subsequent activation of calcium/calmodulin-dependent protein kinase 2 (CaMKII). We find that CaMKII inhibition decreases Wnt synthesis and identify the downregulation of Wntless (WLS) as the basis for this decrease. WLS transports palmitoylated Wnts to the cell surface, and in the absence of Wnts, it undergoes endoplasmic reticulum (ER)-associated degradation (ERAD). CaMKII inhibition increases proteasome-dependent WLS degradation, which can be suppressed by Wnt overexpression, indicating that CaMKII contributes to ER handling of unliganded WLS and prevention of ERAD. CaMKII inhibition also causes a loss of calnexin, an ER stress response through the activation of PERK, and apoptosis in cells expressing high levels of WLS. Moreover, these effects can be prevented by WLS knockdown. The findings reveal a previously unidentified role for CaMKII in supporting ER chaperone functions. They further show that high levels of unliganded WLS could be a potent driver of ER stress in the presence of CaMKII inhibitors, which may have efficacy in tumors expressing high levels of WLS.

Keywords:  CP: cell biology; ER stress response; PERK; UPR; Wnt/β-catenin; Wnt5A; Wntless; apoptosis; calcium/calmodulin-dependent protein kinase 2; calnexin; ruxolitinib

DOI:  https://doi.org/10.1016/j.celrep.2026.117256
PLoS One. 2026 ;21(4): e0347149

Sucralose inhibited cell survival through the activation of ER stress in human endothelial progenitor cells.

Chia-Ying Li, Hung-Yu Lin, En-Pei Isabel Chiang, Hung-Chang Hung, Feng-Yao Tang.

Sucralose, a widely utilized non-caloric sweetener, is frequently added to food and beverage products as a sugar substitute aimed at lowering energy consumption and reducing obesity-related health risks. However, epidemiological studies have indicated a possible association between high intake of sucralose and increased prevalence of coronary artery disease (CAD). Prior research has demonstrated that diminished levels of circulating human endothelial progenitor cells (hEPCs) are linked to a higher risk of CAD. Although sucralose is broadly consumed, its direct biological impact on hEPCs has not been comprehensively characterized. In this study, we investigated the cellular effects of sucralose on hEPCs using a variety of in vitro techniques, including assays for viability, migration, capillary-like tube formation, lactate dehydrogenase (LDH) release-cytotoxicity assay, and protein expression profiling by Western blotting. Our results revealed that increased concentrations of sucralose significantly impaired hEPCs viability, motility, and neovasculogenic function, accompanied by increased expression of markers associated with apoptosis, inflammasome activation, and pyroptosis. Mechanistic analysis further demonstrated that sucralose strongly activated endoplasmic reticulum (ER) stress/PERK pathways in these cells. Inhibition of ER stress via 4-phenylbutyric acid (4-PBA) substantially attenuated sucralose-induced cell death and reduced the expression of pyroptosis-related proteins and inflammasome markers. Taken together, these findings suggest that sucralose disrupts hEPCs function in part by triggering ER stress, which promotes both apoptotic and pyroptotic cell death programs.

DOI: https://doi.org/10.1371/journal.pone.0347149
J Pathol. 2026 Apr 14.

Endoplasmic reticulum stress and the unfolded protein response in lung diseases: molecular pathways and therapeutic interventions.

Lanlan Song, Yichen Liu, Chen Xu, Yaochen Zhang, Kaiming Xu, Dan Yao, Xiaoying Huang.

  Endoplasmic reticulum stress (ERS) occurs when the protein-folding capacity of the endoplasmic reticulum (ER) is overwhelmed, triggering the unfolded protein response (UPR) to restore homeostasis. However, severe or persistent ERS can shift the UPR toward pro-inflammatory, apoptotic, and fibrotic signaling, thereby exacerbating tissue injury. The pathogenesis and progression of lung diseases, which involve highly heterogeneous cell populations, are significantly influenced by these mechanisms. Indeed, ERS and UPR activation are now recognized as central players in the pathophysiology of numerous lung diseases. This review examines the impact of dysregulated ERS/UPR signaling across different lung diseases, with a particular focus on its cell-type-specific effects and disease-specific implications. Furthermore, we discuss emerging therapeutic strategies designed to modulate these pathways. A comprehensive understanding of the cell-type-specific outcomes of ERS/UPR is therefore crucial for developing targeted interventions to mitigate or reverse lung disease progression. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  endoplasmic reticulum; endoplasmic reticulum stress; lung diseases; molecular mechanisms; therapeutic targeting; unfolded protein response

DOI:  https://doi.org/10.1002/path.70058
Nat Cell Biol. 2026 Apr 17.

SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.

Shanshan Liu, Mark Gad, Caifan Li, Kevin Cho, Yuyang Liu, Khando Wangdu, Viktor Belay, Alon Millet, Hiroyuki Kojima, Henry Sanford, Michele Wölk, Linas Urnavicius, Maria Fedorova, Gary J Patti, Ekaterina V Vinogradova, Richard K Hite, Kıvanç Birsoy.

The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 led to GSSG accumulation in the ER and a liposome-based assay demonstrated that SLC33A1 directly transports GSSG. Cryogenic electron microscopy structures and molecular dynamics simulations revealed how SLC33A1 binds GSSG and identified residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induced ER stress and dependency on the ER-associated degradation pathway, driven by a shift in protein disulfide isomerases towards their oxidized forms. Together, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.

DOI: https://doi.org/10.1038/s41556-026-01922-y