bims-unfpre 2025-12-14 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–12–14
eleven papers selected by
Susan Logue, University of Manitoba

Hijacking the unfolded protein response (UPR) pathway: Balancing viral infection and host cell survival.
Endoplasmic reticulum stress and exosomes secretion in the pathogenesis of inflammatory bowel disease: a concise summary of research findings.
Targeting the unfolded protein response for cancer therapy: mitigating tumor adaptation and immune suppression.
Endoplasmic reticulum stress orchestrates cGAS-STING activation in lipid metabolism-associated disorders.
Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy.
circSETD3 confers radiotherapy resistance in nasopharyngeal carcinoma by attenuating ER stress-induced autophagy and apoptosis via PDIA6 upregulation.
Endoplasmic Reticulum Redoxome: Protein Folding and Beyond.
Chemically-induced degradation of the endoplasmic-reticulum stress sensor IRE1 by a VHL-recruiting chimera.
Phosphatidylcholine coordinates ER-autonomous and ER-nonautonomous adaptations to unfolded protein response dysfunction.
Ubiquitination by HRD1 is essential for TLR3 trafficking and its innate immune signaling.
Macrophage PD-1 regulates energy expenditure and metabolic dysfunction under immune checkpoint blockade.

J Biol Chem. 2025 Dec 10. pii: S0021-9258(25)02892-3. [Epub ahead of print] 111040

Hijacking the unfolded protein response (UPR) pathway: Balancing viral infection and host cell survival.

Haoyu Chen, Duxuan Liu, Jing Hua, Mingjie Wu, Yanhong Hua, Chenwei Feng, Zhen He, Peter Moffett, Kun Zhang.

  The endoplasmic reticulum (ER) unfolded protein response (UPR) is a conserved eukaryotic pathway crucial for restoring cellular homeostasis under ER stress. However, diverse viruses infecting mammalian or plant cells strategically hijack and manipulate the UPR pathways featuring sensor proteins IRE1, PERK, ATF6 and bZIP17/28 to promote viral replication . While the UPR is designed to provide cellular adaptive functions in response to stresses, viruses can instead exploit UPR components to instead enhance viral protein folding and remodel ER membranes for viral replication. Exploiting the UPR presents a critical dilemma: while mild UPR activation facilitates virus replication and survival, excessive or prolonged activation triggers host programmed cell death (PCD), prematurely terminating infection. Navigating this UPR tightrope is central for successful infection and replication of the virus. Viruses are not passive triggers of ER stress and the UPR. Viruses have evolved sophisticated "braking mechanisms" to actively modulate UPR signaling intensity. By fine-tuning the UPR, viruses harness the beneficial aspects of the UPR while crucially preventing the activation cascade from reaching the lethal threshold that initiates PCD. By carefully controlling the UPR balance, viruses ensure host cell survival for sufficient duration to maximize viral progeny production. This review details the intricate interactions between the cellular UPR and infecting viruses, including links to cellular clearance pathways like autophagy and ER-associated degradation (ERAD), across different viral families (flaviviruses, coronaviridae, and potyviruses) and hosts (plants and animals). Understanding the sophisticated viral manipulation of the UPR equilibrium reveals fundamental insights into host-pathogen co-evolution and highlights novel potential targets for antiviral strategies aimed at disrupting this delicate balance.

Keywords:  Apoptosis; ER stress; Programed cell death (PCD); Unfold protein response (UPR); Virus

DOI:  https://doi.org/10.1016/j.jbc.2025.111040
Front Pharmacol. 2025 ;16 1702825

Endoplasmic reticulum stress and exosomes secretion in the pathogenesis of inflammatory bowel disease: a concise summary of research findings.

Ashiq Shibili P, Antara Banerjee, Soham Chakraborty, Suresh Babu Kondaveeti, Andrea Porzionato, Silvia Barbon, Surajit Pathak.

  Cellular stress responses and intercellular communication play a crucial role in the pathogenesis of Inflammatory bowel disease (IBD). Among these, endoplasmic reticulum (ER) stress and exosome-mediated signaling have emerged as interconnected drivers of chronic intestinal inflammation. Persistent ER stress, primarily through unfolded protein response pathways involving PERK, IRE1, and ATF6, disrupts epithelial barrier integrity, alters immune cell function, and promotes pro-inflammatory gene expression. ER stress not only affects intracellular homeostasis but also modulates intercellular communication through the secretion of exosomes, which carry proteins, lipids, and nucleic acids. This bidirectional relationship ensures that stress-altered exosomes can amplify ER stress and inflammatory signals in neighboring cells, sustaining intestinal inflammation. For this review, relevant research and review articles were retrieved from established search engines and databases, including PubMed, Google Scholar, and ScienceDirect, using key terms such as "endoplasmic reticulum stress," "exosome secretion," "exosome cargo," "inflammatory bowel disease," "intestinal inflammation," and "intercellular communication." The literature search primarily focused on studies published in the last 5 years, prioritizing clinical and preclinical studies (in vivo and in vitro models). Published literature addressing ER stress, exosome biology, and their interconnection in IBD were included, whereas studies lacking relevance or study quality were excluded. Recent findings highlight a dynamic interconnection between ER stress and exosomes, where ER stress modulates exosome biogenesis, secretion, and cargo composition. In contrast, stress-altered exosomes amplify ER stress signals and inflammatory mediators in neighboring cells. This review aims to summarize the current evidences on the interconnection of ER stress and exosomes in modulating the intestinal microenvironment, driving inflammation, and contributing to epithelial and immune dysregulation in IBD. This review also highlights experimental insights, existing challenges, and therapeutic prospects for targeting the ER stress-exosome axis to restore mucosal homeostasis in IBD management.

Keywords:  endoplasmic reticulum stress; exosomes; immune dysregulation; inflammatory bowel disease; intercellular communication; unfolded protein response

DOI:  https://doi.org/10.3389/fphar.2025.1702825
Biomark Res. 2025 Dec 11. 13(1): 156

Targeting the unfolded protein response for cancer therapy: mitigating tumor adaptation and immune suppression.

Bilal Unal, Fahri Saatcioglu.

  There are significant stress factors within the tumor microenvironment (TME), such as hypoxia, oxidative stress, and nutrient deprivation. These disrupt endoplasmic reticulum (ER) function in cancer cells, as well as the infiltrating immune cells, leading to activation of the unfolded protein response (UPR) signaling, which the tumor uses to mitigate stress and survive. There are three canonical UPR pathways that are regulated by respective ER-resident transmembrane sensors: inositol-requiring protein 1α (IRE1α), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6); activation of these pathways results in expression of cognate transcription factors that regulate gene expression to mitigate ER stress. Persistent UPR activation in the TME has been linked to aberrant tumor growth, progression, metastasis, angiogenesis, and therapy resistance in different cancer types. In addition, modulation of UPR activity significantly impacts immune cell function at different levels further impacting its role on the TME. Therefore, there is now significant interest to design novel therapies that target the UPR to kill cancer cells and simultaneously enhance protective anti-tumor immunity. Here we summarize recent findings as to how targeting UPR signaling can induce tumor regression and at the same time galvanize the immune response. We discuss the potential of integrating UPR targeting with other therapies, such as immune checkpoint inhibition, highlighting emerging strategies to improve therapeutic efficacy and overcome resistance. These recent insights underscore the importance of UPR as a novel therapeutic target for cancer treatment.

Keywords:  ATF6; Cancer; Cancer immunotherapy; Endoplasmic reticulum stress; IRE1alpha; Immune check point inhibitors; PD-1; PERK; Tumor microenvironment; Unfolded protein response

DOI:  https://doi.org/10.1186/s40364-025-00813-y
Int Immunopharmacol. 2025 Dec 05. pii: S1567-5769(25)01956-3. [Epub ahead of print]169 115968

Endoplasmic reticulum stress orchestrates cGAS-STING activation in lipid metabolism-associated disorders.

Qianqian Chen, Minghui Zhang, Sheng Xia.

  Lipid metabolism-associated disorders are pathological states characterized by abnormal levels of lipids and their metabolites, which serve as key drivers of metabolic diseases such as atherosclerosis and diabetes. The endoplasmic reticulum (ER) is primarily recognized for its roles in protein folding and lipid synthesis, and maintaining its homeostasis is crucial for proper cellular function. Emerging evidence indicates that lipid metabolism-associated disorders can disrupt ER homeostasis through multiple mechanisms, leading to ER stress. Persistent ER stress triggers chronic inflammatory responses, thereby accelerating the development of diseases associated with lipid metabolism. Recent studies have demonstrated that chronic inflammation and metabolic dysfunction may be linked to persistent activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Moreover, crosstalk between ER stress and the cGAS-STING signaling pathway has been observed in various metabolic diseases. In this review, we summarize the molecular mechanisms by which lipid metabolism-associated disorders induce ER stress and discuss the regulatory role of ER stress in modulating the STING signaling pathway. Our aim is to provide novel insights into the potential of targeting the ER stress-STING axis for the treatment of metabolic diseases.

Keywords:  Chronic inflammation; Endoplasmic reticulum stress; Lipid metabolism–associated disorders; Metabolic diseases; cGAS–STING pathway

DOI:  https://doi.org/10.1016/j.intimp.2025.115968
Nat Commun. 2025 Dec 12. 16(1): 11094

Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy.

Nicholas D Urban, Shannon M Lacy, Kate M Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, Eric K F Donahue, Kristopher Burkewitz, Matthias C Truttmann.

Cellular systems governing protein folding depend on functional redundancy and diversification to maintain proteostasis. Here, using Caenorhabditis elegans, we show two homologous ER-resident HSP70 chaperones, HSP-3 and HSP-4, have overlapping and distinct roles in ER proteostasis and organismal physiology. Their expression and function vary by tissue, age, and stress, impacting ER stress resistance, reproduction, body size, and lifespan. We also find HSP-3 and HSP-4 uniquely regulate dietary restriction and reduced insulin signaling-mediated longevity in C. elegans. Notably, knockdown of hsp-4, but not hsp-3, induces autophagy and enhances tolerance to protein aggregation stress; this process requires the ortholog of ER-Phagy receptor Sec-62 (C18E9.2) and IRE-1. Finally, human cell data suggests that the dissociation of chaperone Binding Immunoglobulin Protein (BiP) from IRE-1 during times of ER stress promotes autophagy by enhancing the interaction of IRE-1 and Sec-62. These findings reveal how ER chaperone diversification maximizes stress resilience and suggest a BiP-dependent regulation of autophagy.

DOI: https://doi.org/10.1038/s41467-025-65998-0
Oncogene. 2025 Dec 08.

circSETD3 confers radiotherapy resistance in nasopharyngeal carcinoma by attenuating ER stress-induced autophagy and apoptosis via PDIA6 upregulation.

Pingjuan Xiang, Le Tang, Yi Zhang, Juana Jessica Mendoza, Qijia Yan, Lei Shi, Bo Xiang, Zhaoyang Zeng, Pan Chen, Dan Wang, Wei Xiong.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with a high prevalence in Southeast Asia. Although radiotherapy remains the primary treatment modality, resistance to radiation in a subset of patients with advanced-stage disease significantly limits therapeutic outcomes, and the underlying molecular mechanisms remain poorly understood. In this study, we identified the circular RNA circSETD3 as a critical regulator of radioresistance in NPC. Functional assays in both in vitro and in vivo models demonstrated that circSETD3 enhances radioresistance by suppressing autophagy and apoptosis. Mechanistically, circSETD3 binds to the 3' untranslated region (3'UTR) of PDIA6 mRNA, stabilizing the transcript and increasing PDIA6 protein expression and its localization to the endoplasmic reticulum (ER). Elevated PDIA6 promotes the refolding of radiation-induced misfolded proteins, maintains ER proteostasis, and suppresses the unfolded protein response (UPR). This alleviation of ER stress reduces radiation-induced autophagy and apoptosis, ultimately enhancing NPC cell survival under radiotherapeutic stress. Together, these findings reveal a pivotal role for circSETD3 in promoting NPC radioresistance via PDIA6-mediated modulation of endoplasmic reticulum stress, and they provide a novel mechanistic framework and promising therapeutic target for improving radiotherapy efficacy in NPC.

DOI: https://doi.org/10.1038/s41388-025-03652-1
Biochemistry. 2025 Dec 12.

Endoplasmic Reticulum Redoxome: Protein Folding and Beyond.

Percillia V S Oliveira, Tiphany C De Bessa, Francisco R M Laurindo.

  The endoplasmic reticulum (ER), the largest cellular organelle, is crucially dependent on its redox organization. First, to optimize disulfide bond formation in nascent proteins, it maintains a relatively oxidizing environment, reminiscent of the extracellular space. Second, it harbors several oxidoreductases from the protein disulfide isomerase (PDI) family, together with Ero1α oxidase and chaperones, which compose interplaying oxidative, reductive, and chaperone pathways to optimize protein processing. Third, disulfide formation and reshuffling in client proteins, involving thiol oxidation and disulfide exchange reactions, connect proteostasis to ER/cellular redox homeostasis. ER redox folding involves Ca2+-dependent liquid phase separation of PDI complexes. Calcium fluxes heavily interplay with dynamic redox regulation. ER stress disrupts the ER redox state and, in turn, is also regulated by cellular redox processes. Moreover, the ER makes membrane contacts with many other organelles such as plasma membrane, peroxisomes, and mitochondria, which are hubs for mutually dependent oxidant and calcium-linked effects. Furthermore, the ER redoxome extends to other subcellular and extracellular locations, a process we termed the "ER-dependent outreach redoxome (ERDOR)". ERDOR can occur by overflow of ER products such as H2O2, mobility of ER-associated domains or, mainly, via ER oxidoreductase translocation. The ER establishes a particular communication with the extracellular milieu via translocation of PDIs. Despite the low levels of extracellularly located ER oxidoreductases, they redox-regulate several molecular targets and may compose a peri/epicellular redox network. This article provides a comprehensive overview of the ER redoxome as an important emerging frontier to understand not only redox proteostasis but also intra- and intercellular redox communication.

Keywords:  NADPH oxidase; NOX; oxidants; phenotype; protein disulfide isomerase; vascular smooth muscle cells

DOI:  https://doi.org/10.1021/acs.biochem.5c00527
Nat Commun. 2025 Dec 11.

Chemically-induced degradation of the endoplasmic-reticulum stress sensor IRE1 by a VHL-recruiting chimera.

Jin Du, Elisia Villemure, Matthew Johnson, Caleigh Azumaya, Catarina J Gaspar, Scot Marsters, David Lawrence, Scott Foster, Alexis Rohou, Tommy K Cheung, Christopher M Rose, Thomas Garner, Soo Ro, Kevin Clark, Maureen H Beresini, Marie-Gabrielle Braun, Joachim Rudolph, Peter Hsu, Avi Ashkenazi.

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-endoribonuclease and scaffolding activities. Cancer cells often co-opt IRE1 to facilitate growth. An IRE1-RNase inhibitor has entered clinical trials; however, recent work uncovered a significant nonenzymatic IRE1 dependency in cancer. To fully disrupt IRE1, we describe a proteolysis-targeting chimera (G6374) that couples an IRE1-kinase ligand to a compound that binds the ubiquitin Cullin-RING Ligase (CRL) substrate receptor, VHL. G6374 induces a stable, cooperative interaction between IRE1 and VHL, driving K48-linked ubiquitination on two principal lysine residues in the IRE1-kinase domain and inducing proteasomal IRE1 degradation. Cryogenic electron microscopy and mutagenesis studies reveal a 2:2 IRE1:VHL ternary-complex topology and critical interactional features, informing future designs. G6374 blocks growth of IRE1-dependent cancer cells irrespective of their dependency mode, while sparing IRE1-independent cells. We provide a proof-of-concept for VHL-based degradation of an ER-transmembrane protein, advancing strategies to fully disrupt IRE1.

DOI: https://doi.org/10.1038/s41467-025-66382-8
J Biol Chem. 2025 Dec 06. pii: S0021-9258(25)02878-9. [Epub ahead of print] 111026

Phosphatidylcholine coordinates ER-autonomous and ER-nonautonomous adaptations to unfolded protein response dysfunction.

Haixiang Tong, Wei Li, Pangui Yuan, Xinyu Wang, Shanshan Pang, Haiqing Tang.

  The ER UPR plays a crucial role in maintaining proteostasis, with its dysfunction closely associated with aging and various diseases. However, how cells cope with ER UPR dysfunction remains largely unexplored. Here, we report that both ER-autonomous and ER-nonautonomous adaptive responses are activated by defects in the IRE-1/XBP-1 UPR branch in C. elegans. IRE-1/XBP-1 dysfunction not only triggers the activation of the PEK-1 UPR branch but also induces a lysosome-dependent cytosolic proteostatic response. Mechanistically, IRE-1/XBP-1 dysfunction downregulates phosphatidylcholine (PC) metabolism, reducing levels of membrane lipid PC. This PC deficiency drives BORC complex recruitment to lysosomes, triggering lysosomal activation. Furthermore, suppression of phosphatidylcholine metabolism alone sufficiently activates both the ER UPR and lysosomal pathways, thereby enhancing resilience to proteostatic stress and contributing to longevity. These findings provide insights into how cells integrate distinct adaptive responses to maintain systemic proteostasis when the ER UPR is compromised and identify phosphatidylcholine as a potent regulator of proteostasis and aging.

Keywords:  UPR; aging; lysosome; phosphatidylcholine; proteostasis

DOI:  https://doi.org/10.1016/j.jbc.2025.111026
Nat Commun. 2025 Dec 10.

Ubiquitination by HRD1 is essential for TLR3 trafficking and its innate immune signaling.

Lianfeng Zhao, Zinan He, Yao Sun, Mengqi Sun, Zheyi Liu, Zhangsen Zhou, Ling Qi, Yuan Luo, Yewei Ji, Tingbo Liang.

Toll-like receptor 3 (TLR3), an innate immune sensor for double-stranded RNA (dsRNA), traffics from the endoplasmic reticulum (ER) after synthesis to endolysosomes for proteolytic cleavage and activation. However, the molecular mechanisms governing TLR3 trafficking remain largely unclear. Here, we identify the ER-resident E3 ligase HMG-CoA reductase degradation protein 1 (HRD1), a core component of ER-associated degradation (ERAD), as a key regulator that promotes TLR3 trafficking and downstream signaling. HRD1 deficiency in macrophages significantly impairs poly(I:C)-induced TLR3 signaling and inflammatory responses in vitro and in vivo, caused by a marked reduction in TLR3 transport into endolysosomes and subsequent proteolytic processing. Mechanistically, HRD1 mediates ubiquitination of ER-localized TLR3 at lysine 813, which is required for its recognition and sorting by the endosomal sorting complex required for transport (ESCRT) machinery. This HRD1 function is decoupled from its canonical ERAD activity and the ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α). Hence, our study identifies a previously unrecognized mechanism controlling TLR3 signaling and links HRD1-mediated ubiquitination to immune sensor trafficking during innate immune responses.

DOI: https://doi.org/10.1038/s41467-025-67219-0
Cell Metab. 2025 Dec 10. pii: S1550-4131(25)00493-0. [Epub ahead of print]

Macrophage PD-1 regulates energy expenditure and metabolic dysfunction under immune checkpoint blockade.

Ming-Ming Wu, Yan-Chao Yang, Zhi-Qiang Hu, Jie-Yu Chang, Han Xiao, Chang Miao, Bo-Wen Zhang, Zhi-Xi He, Di Zhu, Yu-Ran Duan, Shuo Wang, Jian-Yu Liu, Zhan-Peng Guo, Yu Sun, Dan-Yang Liu, Miao Yu, Yue Zhang, Jian-Jun Mao, Shuai Jiang, Bing-Kun Zhang, Zhu Mei, Jun Gao, Chen Liang, Qiu-Shi Wang, Chang-Jiang Yu, Dan Zhao, Cheng-Hui Yan, Yue Li, Zhen-Wei Pan, Zheng Chen, Da-Qian Xu, Tong Liu, Yong Ji, Zhi-Ren Zhang.

  Immune checkpoint inhibitor (ICI) therapies increase the risk of metabolic syndrome; the underlying mechanisms remain elusive. We show that an anti-PD-1 antibody targets macrophage PD-1 to reduce energy expenditure without affecting food intake, augmenting the susceptibility of mice to high-fat diet (HFD)-induced obesity and systemic metabolic disorders. Mechanistically, lipopolysaccharide (LPS) activates Unc-51-like autophagy activating kinase 1 (ULK1) in a mammalian target of rapamycin (mTOR)-dependent manner. Activated ULK1 phosphorylates PD-1 at Thr250 to inhibit FBXO38-mediated PD-1 ubiquitination and degradation by disrupting FBXO38-PD-1 binding. Phosphorylated PD-1 interacts with inositol-requiring enzyme 1α (IRE1α) and attenuates IRE1α autophosphorylation to suppress endoplasmic reticulum (ER) stress-mediated inflammatory responses. Suppressing IRE1α alleviates HFD-induced metabolic disorders in macrophage-specific PD-1 knockout mice by rescuing the reduced energy expenditure. Our findings highlight the critical role of macrophage PD-1 at the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction. The underscored moonlighting function of macrophage PD-1 may provide a new rationale for combating ICI therapy- and HFD-induced metabolic diseases.

Keywords:  ER stress; IRE1α; macrophage PD-1; metabolic diseases; obesity

DOI:  https://doi.org/10.1016/j.cmet.2025.11.009