bims-unfpre 2025-07-27 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–07–27
seven papers selected by
Susan Logue, University of Manitoba

PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.
Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy.
Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis.
Inhibition of anti-apoptotic Bcl-2 family members promotes synergistic cell death with ER stress inducers by disrupting autophagy in glioblastoma.
Endoplasmic reticulum-targeted strategies for programmed cell death in cancer therapy: Approaches and prospects.
UPR-induced intracellular C5aR1 promotes adaptation to the hypoxic tumour microenvironment.
Stressful situations: molecular insights on mitochondrial quality control pathways.

J Biol Chem. 2025 Jul 21. pii: S0021-9258(25)02354-3. [Epub ahead of print] 110504

PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.

Shixin Zhou, Zihan Zhou, Si Chen, Ming Wang, Likun Wang.

  The unfolded protein response (UPR) initiated under endoplasmic reticulum (ER) stress can not only maintain the ER homeostasis, but also modulate the secretion of proteins and lipids that transmit ER stress signals among cells. Exosomes are multivesicular body (MVB)-derived extracellular vesicles, constituting the unconventional protein secretion pathway. Whether and how the secretion of exosomes is regulated by the UPR remains largely unknown. Here, we reported that ER stress induces exosome secretion in an UPR-dependent way. Activation of PERK and IRE1α, two of the UPR branches, represses the acidification and catabolic activity of lysosomes. This blocked MVB-lysosome fusion, re-directing MVBs from lysosomal degradation to plasma membrane fusion, resulting in exosome release. Calcium-mediated activation of PERK, in the absence of ER stress, is sufficient to suppress lysosomal degradation and augment exosome secretion, partly through its downstream factor ATF4. Our study revealed a function of PERK and IRE1α in modulating lysosome activity and dictating the fate of MVBs, facilitating cell-cell communication via exosomes.

Keywords:  IRE1α; PERK; extracellular vesicle; lysosome; unfolded protein response

DOI:  https://doi.org/10.1016/j.jbc.2025.110504
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2412246122

Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy.

Amy S Lee.

  Since their discoveries in the 1960s as a family of proteins produced by cells in response to stress, molecular chaperones are increasingly recognized as major regulators of cellular homeostasis in health and disease. Among the heat shock protein 70 family, the 78-kDa glucose-regulated protein (GRP78), also referred to as BiP and encoded by the HSPA5 gene, contains a signal peptide targeting it into the endoplasmic reticulum (ER). Through its interaction with the transmembrane ER stress sensors, GRP78 acts as a master regulator of the Unfolded Protein Response (UPR) which allows cells to adapt to stress observed in many human diseases. The discovery that ER stress not only upregulates GRP78 to cope with ER protein quality control but also actively promotes its relocation to other cellular compartments where they vastly expand its functional repertoire beyond the ER represents a paradigm shift. This Perspective describes the origin and linkage of GRP78 to the UPR and the mechanisms whereby ER stress actively promotes export of GRP78 from the ER, as exemplified by its translocation to the cell surface where it acts as a multifaceted receptor and a conduit for drug and viral entry, as well as its translocation into the nucleus, where it assumes the surprising role of a transcriptional regulator whereby reprogramming the cell's transcriptome. Furthermore, this Perspective addresses how these and other atypical localizations of GRP78 impact human disease, with emphasis on cancer and COVID-19, and the exciting prospect that drugs targeting GRP78 could dually suppress tumorigenesis and viral infections.

Keywords:  ER stress; GRP78/BiP; cancer; chaperone; translocation

DOI:  https://doi.org/10.1073/pnas.2412246122
Glia. 2025 Jul 20.

Endoplasmic Reticulum Stress Amplifies Cytokine Responses in Astrocytes via a PERK/eIF2α/JAK1 Signaling Axis.

Anirudhya Lahiri, Savannah G Sims, Jessica A Herstine, Alicia Meyer, Micah J Marshall, Ishrat Jahan, Subhodip Adhicary, Allison M Bradbury, Gordon P Meares.

  Aberrant activation of multiple cellular processes and signaling pathways is a hallmark of many neurological disorders. Understanding how these processes interact is crucial for elucidating the neuropathogenesis of these diseases. Among these, endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and neuroinflammation are frequently implicated. Previously, we demonstrated that ER stress synergizes with tumor necrosis factor (TNF)-α to amplify interleukin (IL)-6 and C-C motif chemokine ligand (CCL)20 production in astrocytes through a Janus kinase 1 (JAK1)-dependent mechanism. Here, we expand on this finding by defining the scope and underlying mechanisms of this phenomenon. We show that ER stress and TNF-α cooperatively enhance inflammatory gene expression in astrocytes via a signaling axis that requires both protein kinase R (PKR)-like ER kinase (PERK) and JAK1. PERK-mediated phosphorylation of eukaryotic translation initiation factor (eIF)2α suppresses protein translation, delaying the expression of negative regulators such as NF-κB inhibitor (IκB)α and suppressor of cytokine signaling (SOCS)3 following TNF-α or oncostatin M (OSM) stimulation, respectively. Pharmacological reversal of p-eIF2α-dependent translational suppression using the small molecule integrated stress response inhibitor (ISRIB) restored IκBα and SOCS3 expression and attenuated the ER stress-induced enhancement of TNF-α- or OSM-driven inflammatory responses. Notably, astrocytes harboring a vanishing white matter-associated EIF2B5 mutation revealed that translational attenuation alone is insufficient to amplify cytokine-induced gene expression. Together, these findings identify a PERK/eIF2α/JAK1 signaling axis that sensitizes astrocytes to inflammatory cytokines, providing new mechanistic insights into the interactions between ER stress and neuroinflammation.

Keywords:  IL‐6; JAK/STAT; glia; integrated stress response; neuroinflammation; unfolded protein response

DOI:  https://doi.org/10.1002/glia.70067
Cell Death Discov. 2025 Jul 24. 11(1): 340

Inhibition of anti-apoptotic Bcl-2 family members promotes synergistic cell death with ER stress inducers by disrupting autophagy in glioblastoma.

Tianyi Huang, Satoshi Takagi, Sumie Koike, Ryohei Katayama.

Glioblastoma (GBM) remains one of the most aggressive and challenging brain tumors. Unfortunately, current clinical treatment options offer limited efficacy, highlighting the necessity for uncovering novel therapeutic strategies. Here, monotherapy and combination library screening were employed, and identified that the efficacy of obatoclax, a pan-Bcl-2 family inhibitor, was improved significantly when combined with ER-stress inducers, including tunicamycin. Combinatorial knockdown of anti-apoptotic proteins confirmed that the loss of Mcl-1 and Bcl-xL synergistically enhanced apoptosis under ER stress conditions. Although ER stress inducers triggered the stress response in GBM cells, obatoclax co-treatment enhanced this response by upregulating ATF-4 and CHOP, which promoted apoptosis along with increased caspase 3/7 activity and cleavage of PARP. ATF-4 knockdown significantly decreased the apoptosis induced by obatoclax and tunicamycin co-treatment and reduced the expression of CHOP and BIM. Under ER stress responses, GBM cells exerted an autophagy response to recover from the stress condition; however, obatoclax co-treatment disrupted the autophagy responses, particularly by disrupting autophagic cargo degradation. Our findings suggest that targeting Mcl-1 and Bcl-xL, coupled with ER-stress induction, could be a promising strategy for the treatment of GBM, highlighting the potential for combination therapies involving pan-Bcl-2 family inhibitors to overcome current limitations in the treatment of GBM.

DOI: https://doi.org/10.1038/s41420-025-02632-4
J Control Release. 2025 Jul 21. pii: S0168-3659(25)00681-9. [Epub ahead of print] 114059

Endoplasmic reticulum-targeted strategies for programmed cell death in cancer therapy: Approaches and prospects.

Li Liang, Zhu Zhu, Xiaohe Jiang, Yan Tang, Jiaxin Li, Zilong Zhang, Bingwen Ding, Xiang Li, Miaorong Yu, Yong Gan.

  The endoplasmic reticulum (ER) plays a dual role in cancer biology, functioning both to preserve cellular homeostasis and to facilitate pathological progression. Rapidly proliferating cancer cells, which exhibit heightened metabolic activity, frequently experience ER stress that activates the unfolded protein response (UPR), a mechanism that promotes cellular adaptation and survival. However, when ER stress is prolonged or excessive, it can shift the balance toward programmed cell death (PCD), including apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Given the ER's central role in regulating proteostasis and stress signaling, therapeutically targeting the ER presents a compelling strategy to disrupt cancer cell survival and overcome treatment resistance. Nanomedicine, particularly the use of nanoparticles (NPs) for precise ER targeting, offers a promising platform to modulate ER function and trigger PCD in cancer cells. In this review, we highlight recent advances in the design guidelines of ER-targeted NPs, with a focus on their capacity to engage and activate PCD pathways in cancer cells. We further discuss the current limitations and emerging opportunities in this field, aiming to inform the development of next-generation ER-targeted delivery platforms for enhanced efficacy in cancer treatment.

Keywords:  Anti-cancer therapy; Endoplasmic reticulum; Nanoparticle; Programmed cell death; Targeted drug delivery

DOI:  https://doi.org/10.1016/j.jconrel.2025.114059
Cell Death Dis. 2025 Jul 22. 16(1): 547

UPR-induced intracellular C5aR1 promotes adaptation to the hypoxic tumour microenvironment.

Tatsuya Suwa, Kelly Sw Lee, Ian J Chai, Heather O L Clark, David J MacLean, Nicole Machado, Gonzalo Rodriguez-Berriguete, Lolita Singh, Geoff S Higgins, Ester M Hammond, Monica M Olcina.

Dysregulation of the C5a-C5a receptor 1 (C5aR1) signalling axis underlies inflammation and immune-driven pathology. C5aR1 was traditionally thought to be primarily expressed on the cell membrane, although recent reports indicate the importance of intracellular C5aR1 expression for the inflammatory effector functions of various cell types. However, the mechanisms regulating C5aR1 expression and localisation remain unclear. In tumours with an immunosuppressive microenvironment, we recently found C5aR1 expression on malignant epithelial cells, highlighting potential tumour cell-specific functions. Here, we show that physical conditions of the tumour microenvironment leading to immunosuppression, induce C5aR1 expression and control its intracellular localisation. Mechanistically, we find that low oxygen (hypoxia) induces C5aR1 expression in an unfolded protein response (UPR)-dependent manner via enhanced endoplasmic reticulum stress. Furthermore, hypoxia drives endocytosis, relocating C5aR1 from the cell membrane to the intracellular compartment. By genetically and pharmacologically targeting the C5a/C5aR1 axis, we show that C5aR1 mediates cellular adaptation to hypoxia by regulating processes associated with cell fate, including autophagy and apoptosis. In line with hypoxia-induced intracellular C5aR1 pools, the most significant pharmacological effects on cell survival are observed with selective small molecule inhibitors of C5aR1 associated with high cell permeability. These results suggest that the dysregulated C5a/C5aR1 axis and the hypoxia-induced shift in C5aR1 localisation support tumour cell survival in the hypoxic tumour microenvironment and provide new insights into therapeutic strategies for targeting the C5a/C5aR1 axis in cancer.

DOI: https://doi.org/10.1038/s41419-025-07862-z
J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02333-6. [Epub ahead of print] 110483

Stressful situations: molecular insights on mitochondrial quality control pathways.

Sabrina Romanelli, Jean-François Trempe.

Mitochondrial quality control has emerged as an important area of research over the past decade, with more than 2,000 publications exploring the molecular pathways that regulate it. Mitochondria are essential for energy production and various cellular functions but are highly susceptible to damage from stressors such as protein misfolding, reactive oxygen species, and chemicals that disrupt the electron transport chain. If left unresolved, mitochondrial dysfunction can lead to health complications, including neurodegenerative disorders, cardiovascular diseases, and cancer. To maintain cellular health, cells evolved quality control pathways to remove damaged mitochondrial components. This review focuses on three key quality control responses: the PINK1-Parkin pathway, the DELE1-HRI pathway, and the mitochondrial unfolded protein response (UPRmt). While these pathways have distinct functions, there is ongoing debate about how they overlap and which responds first in different contexts. In this review, we discuss the physiological and structural mechanisms behind each pathway, explore how they interconnect, and highlight their differences and relevance to disease. By summarizing this information in a single review, we aim to enhance the molecular understanding of mitochondrial quality control, which can help highlight avenues for novel therapeutics for diseases associated to dysfunctional mitochondria.

DOI: https://doi.org/10.1016/j.jbc.2025.110483