bims-unfpre 2025-07-20 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–07–20
eleven papers selected by
Susan Logue, University of Manitoba

The endoplasmic reticulum proteostasis network and bone disease.
ATF-4 deficiency increases ER stress and induces osteoarthritis formation in mice.
Targeting the canonical ER stress IRE1α/XBP1 pathway counteracts pancreatic cancer-induced skeletal muscle wasting.
Somatic mutations in IRE1α regulate keratinocyte migration and survival by differentially activating Rho GTPases.
DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.
Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer.
Differential ER stress responses during lactation and postpartum outcomes in mice depending on their mitochondrial genotype.
Neuronal SEL1L-HRD1 ERAD regulates one-carbon metabolism and is essential for motor function and survival.
IFNγ augments TKI efficacy by alleviating protein unfolding stress to promote GSDME-mediated pyroptosis in hepatocellular carcinoma.
IRE1α and IRE1β Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms.
Emerging roles for integrated stress response signaling in homeostasis.

Trends Mol Med. 2025 Jul 10. pii: S1471-4914(25)00145-5. [Epub ahead of print]

The endoplasmic reticulum proteostasis network and bone disease.

Hesso Farhan, Muhammad Zahoor, Josephine T Tauer, Wolfgang Högler.

  Bone homeostasis relies on the coordinated activity of osteoblasts and osteoclasts that balances bone formation and resorption, and of osteocytes for biomechanical sensing and hormone secretion. A key factor in the function of these cells is proteostasis, where the endoplasmic reticulum (ER) oversees protein synthesis, quality control, folding, and the secretion of proteins such as collagen type I. Emerging research links ER proteostasis defects to skeletal disorders caused by impaired bone development and mass. We explore the mechanisms of ER proteostasis, including the unfolded protein response (UPR), and discuss how genetic, metabolic, and environmental factors disrupt these pathways and contribute to bone pathology. We also highlight the need for further mechanistic insights which could pave the way for novel therapies that target ER-Golgi traffic and inhibit ER stress in bone diseases.

Keywords:  COPII; endoplasmic reticulum; osteogenesis imperfecta; proteostasis; skeletal dysplasia; unfolded protein response

DOI:  https://doi.org/10.1016/j.molmed.2025.06.005
Mol Cell Biochem. 2025 Jul 12.

ATF-4 deficiency increases ER stress and induces osteoarthritis formation in mice.

Peng-Yu Xie, Shan-Shan Li, Xu Liang, Hang Ma, Ying-Chao Yang, Tian-Fang Li.

  Although osteoarthritis (OA) is a leading cause of morbidity, no disease-modifying osteoarthritis drugs (DMOADs) are currently available. An in-depth understanding of OA pathogenesis may help the development of novel and effective treatments. Activating transcription factor 4 (ATF-4) plays a critical role in skeletal biology as it is closely involved in ER stress, autophagy, cell senescence, etc. Our study showed that meniscal injury in Atf-4 deficient (Atf-4-/-) mice resulted in complete destruction of mouse knee joints. In addition, these mice developed spontaneous OA-like lesions with aging. In vitro study demonstrated that the ER stress was increased and proliferation was decreased in articular chondrocytes from Atf-4-/- mice compared to wild-type (WT) chondrocytes, which enhanced apoptosis of Atf-4-/- chondrocytes. Re-introduction of ATF-4 into the joint cavity of Atf-4-/- mice significantly alleviated joint damage. Taken together, our study demonstrates that ATF-4 is a critical molecule for normal functionality of articular chondrocytes and its modification may facilitate the identification of novel therapeutic targets.

Keywords:  ATF-4; Chondrocyte; ER stress; Osteoarthritis

DOI:  https://doi.org/10.1007/s11010-025-05349-1
bioRxiv. 2025 May 05. pii: 2025.05.05.652304. [Epub ahead of print]

Targeting the canonical ER stress IRE1α/XBP1 pathway counteracts pancreatic cancer-induced skeletal muscle wasting.

Aniket S Joshi, Meiricris Tomaz da Silva, Anh Tuan Vuong, Bowen Xu, Ravi K Singh, Ashok Kumar.

Cancer-driven cachexia is a deleterious syndrome which involves progressive loss of skeletal muscle mass with or without fat loss, fatigue, and weakness that cannot be reversed by nutritional intake. Recent studies have shown deregulation of endoplasmic reticulum (ER)-induced unfolded protein response (UPR) pathways in skeletal muscles in various catabolic conditions, including cancer growth. However, the role of individual arms of the UPR in regulation of muscle mass remains poorly understood. Here, we demonstrate that the IRE1α/XBP1 arm of the UPR stimulates the activation of ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid oxidation in skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Furthermore, our results show that IRE1α/XBP1 pathway is a key contributor to cachexia as targeted ablation of XBP1 transcription factor in mouse skeletal muscle inhibits KPC tumor-induced muscle wasting. Transcriptionally active XBP1 protein binds to the promoter region of multiple genes whose products are involved in skeletal muscle wasting. Treatment of KPC tumor-bearing mice with 4µ8C, a small molecule IRE1α inhibitor, reverses cachexia-induced molecular changes and improves skeletal muscle mass and strength. Altogether, our study highlights that the IRE1α/XBP1 signaling axis mediates pancreatic cancer-induced muscle wasting and inhibition of this pathway could be a potential approach to mitigate muscle wasting in pancreatic cancer patients.

DOI: https://doi.org/10.1101/2025.05.05.652304
J Cell Sci. 2025 Jul 14. pii: jcs.263790. [Epub ahead of print]

Somatic mutations in IRE1α regulate keratinocyte migration and survival by differentially activating Rho GTPases.

Saie Mogre, Lily Robinson, Komal Sethia, Bipin Rimal, Jeongin Son, Christian Pacifico, Lorraine Santy, Andrew Patterson, Adam B Glick.

  IRE1α is an Endoplasmic Reticulum (ER) transmembrane protein with cytoplasmic kinase and endoribonuclease (RNase) domains. Under ER stress, IRE1α can splice Xbp1 mRNA enabling translation of this Unfolded Protein Response transcription factor or mediate sequence-specific degradation of mRNAs through Regulated IRE1α-Dependent Decay (RIDD). Somatic mutations in IRE1α occur in many different human cancers including non-melanoma skin cancers (NMSC). To understand their role in skin cancer pathogenesis, we generated immortalized primary mouse keratinocytes inducibly expressing multiple engineered and cancer-associated mutations, including those present in NMSC. All NMSC mutations tested were activating mutations with elevated autophosphorylation and enhanced RIDD activity relative to Xbp1 splicing. Pathway analysis of RNA-Seq data and in vitro studies showed that RNase-impaired mutations enhanced cell migration due to increased levels of active RhoA and a RIDD target, Angptl4. In contrast, activating mutations exhibited elevated Rac1 activation, enrichment of genes involved in DNA repair, increased phospho-ATR levels, and improved survival in response to UVB irradiation, a critical etiological factor for sun-exposed skin cancers. Together, these results suggest divergent roles of IRE1α mutations by mediating critical tumor-promoting events in keratinocytes.

Keywords:  ER Stress; IRE1α; Migration; RIDD; UV-induced apoptosis

DOI:  https://doi.org/10.1242/jcs.263790
bioRxiv. 2025 Jun 09. pii: 2025.06.08.658532. [Epub ahead of print]

DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.

Abd-El Monsif A Shawky, Allison Scarboro, Josef Mick, Mahmoud Dondeti, Kenneth Avanzino, Constantine A Simintiras, Maria Hatzoglou, Anastasios Vourekas.

In eukaryotes, regulation of mRNA translation initiation greatly impacts gene expression, and is critical for cellular stress responses. DDX3X is a ubiquitous DEAD-box RNA helicase whose precise role in 5' UTR scanning and start codon decoding in non-stressed and stressed cells is still elusive. Here we show that DDX3X engages with thousands of mRNAs as part of the eIF4F-mediated 48S scanning complex, simultaneously acting to promote or suppress translation of select mRNAs in non-stressed conditions, and switches this regulation in opposite directions in acute ER stress. We find distinct DDX3X binding patterns of differentially regulated mRNAs, which lead us to identify N4-acetylation of cytidines surrounding the start codon as an accompanying feature of mRNAs subject to DDX3X-mediated selective dual regulation. Our findings illuminate the role of DDX3X in stress response and highlight a novel connection between an RNA helicase and a post-transcriptional modification in regulating mRNA translation.

DOI: https://doi.org/10.1101/2025.06.08.658532
J Crohns Colitis. 2025 Jul 03. pii: jjaf102. [Epub ahead of print]19(7):

Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer.

Janine Kövilein, Adam Sorbie, Sevana Khaloian, Vanessa Küntzel, Miriam von Stern, Mohamed Ahmed, Sebastian Jarosch, Marianne Remke, Amira Metwaly, Elena M Reuss, Dirk H Busch, Matthieu Allez, Katja Steiger, Barbara Schraml, Olivia I Coleman, Dirk Haller.

   BACKGROUND AND AIMS: Chronic inflammation in inflammatory bowel disease (IBD) patients represents a risk factor for developing colitis-associated cancer (CAC). We previously linked the endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) with spontaneous microbiota-dependent colonic adenoma development in mice expressing epithelial-specific activated ATF6 (nATF6IEC).
METHODS: To investigate IBD-related risk factors in ATF6-mediated tumorigenesis, we crossed tumor-free monoallelic (tg/wt) nATF6IEC mice with interleukin-10 deficient mice (Il10-/-). We characterized our newly generated murine model under germ-free (GF) and specific pathogen-free (SPF) conditions, including tumor phenotype and immune cell characterizations, as well as complex human stool and minimal consortium colonizations.
RESULTS: IL-10 deficiency initiated tumor susceptibility, with 77% of 12-week tg/wt;Il10-/- mice developing colonic adenomas and invasive carcinomas in this novel CAC mouse model. Tumor formation correlated with mucosal immune cell infiltration, characterized by CD11b+ granulocytes and monocytes, and mucosa-associated dysbiosis. Colonization of germ-free nATF6IEC;Il10-/- mice with minimal biosynthetic consortia and IBD stool re-established CAC, confirming microbiota-dependent ATF6-driven tumorigenesis. Increased ATF6 expression in IBD patients during active disease highlights human relevance.
CONCLUSION: Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis.

Keywords:  ER stress; IBD-relevant minimal consortium; activating transcription factor 6; colitis-associated cancer; human microbiota associations

DOI:  https://doi.org/10.1093/ecco-jcc/jjaf102
Nat Commun. 2025 Jul 11. 16(1): 6432

Differential ER stress responses during lactation and postpartum outcomes in mice depending on their mitochondrial genotype.

Mrittika Chattopadhyay, Edmund Charles Jenkins, William Janssen, Thelma Mashaka, Doris Germain.

Breastfeeding protects against breast cancer in some women but not others, however the mechanism remains elusive. Lactation requires intense secretory activity of the endoplasmic reticulum for the production of milk proteins and endoplasmic reticulum- mitochondria contacts for lipid synthesis. We show that in female mice that share the same nuclear genome (BL/6) but differ in mitochondrial genomes (C57 or NZB), lactation engages different transcriptional programs resulting in anti-tumorigenic lactation in BL/6C57 females and pro-tumorigenic lactation in BL/6NZB females. Our data indicate activation of a pro-apoptotic endoplasmic reticulum-stress response during lactation in BL/6C57 females, which is not observed in BL/6NZB females. Single cell sequencing identified a sub-population of cells, uniquely amplified during lactation in BL/6NZB females, that shares the genetic signature of post-partum breast cancer in humans and is characterized by cell cycle markers and loss of p53. We show that pharmacological manipulations of endoplasmic reticulum-stress directly affect this signature. Overall, our data suggest the unexpected differential nature of lactation and its potential impact on the risk of the development of post-partum breast cancer.

DOI: https://doi.org/10.1038/s41467-025-61666-5
bioRxiv. 2025 Jun 18. pii: 2025.06.16.659938. [Epub ahead of print]

Neuronal SEL1L-HRD1 ERAD regulates one-carbon metabolism and is essential for motor function and survival.

Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang Leo Lin, Jiwon Hwang, Alan Rupp, Abigail Tomlinson, Andrew J Scott, Zhen Zhao, Daniel R Wahl, Martin Myers, Costas A Lyssiotis, Ling Qi.

Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice ( Sel1L SynCre ) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age-mirroring core clinical features observed in affected patients-despite preserved neuronal numbers and only modest ER stress. Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulted from induction of the integrated stress response (ISR). Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing new insight into the molecular basis of ERAD-related neurodevelopmental disease.
Summary: Using a neuron-specific Sel1L knockout mouse model, we demonstrate that Sel1L deficiency activates integrated stress responses, rewires one-carbon metabolism, and impairs motor function and survival.

DOI: https://doi.org/10.1101/2025.06.16.659938
Cell Death Dis. 2025 Jul 11. 16(1): 512

IFNγ augments TKI efficacy by alleviating protein unfolding stress to promote GSDME-mediated pyroptosis in hepatocellular carcinoma.

Xiaoxiao Li, Fujia Lu, Jie Zhou, Xiong Li, Yan Li, Weijie Ye, Jing Li, Liguo Yang, Shi Tang, Yuhan Zhou, Songlin Yin, Yuan Gao, Haotian Shang, Tengfei Chao, Xiang Cheng, Qian Chu, Weimin Wang.

Tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced hepatocellular carcinoma (HCC). However, their therapeutic efficacy is often limited by drug resistance, primarily driven by tumoral intrinsic mechanisms. In this study, we demonstrate that IFNγ in the tumor microenvironment can potentiate TKI response, and that ablation of IFNγ receptor on HCC cells leads to TKI resistance in vivo. Mechanistically, IFNγ synergizes with TKI to induce GSDME-mediated pyroptosis of HCC cells. The PERK-mediated unfolded protein response (UPR) protects HCC cells from TKI-induced pyroptosis. IFNγ attenuates PERK activation by inducing the expression of PDIA1, which alleviates the stress of protein unfolding. In vivo, PERK inhibition augments TKI therapy, and elevated PERK expression correlates with poor overall survival of patients with HCC. Moreover, IFNγ-producing CD8+ T cells can potentiate TKI efficacy. Combining PD-1 blockade to activate T-cell response with TKI therapy synergistically suppresses the growth of GSDME-expressing HCC tumors, which is further enhanced by the PERK inhibitor. Our findings reveal how IFNγ signaling modulates TKI response and demonstrate the potential of a sequential combination of ICB-mediated immunotherapy and TKI therapy for patients with GSDME+ HCC. T cell-derived IFNγ enhances TKI-induced pyroptosis in HCC. Mechanistic illustration of IFNγ secreted from CD8+ T cells enhancing TKI-induced GSDME-mediated pyroptosis in hepatocellular carcinoma via suppression of the PERK pathway. Created with BioRender.com.

DOI: https://doi.org/10.1038/s41419-025-07839-y
bioRxiv. 2025 May 07. pii: 2025.05.01.651751. [Epub ahead of print]

IRE1α and IRE1β Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms.

Ruishu Deng, Miao Wang, Thanyarat Promlek, Clementine Druelle-Cedano, Rabi Murad, Nicholas O Davidson, Randal J Kaufman.

Intestinal epithelial cells (IECs) uniquely express two IRE1 paralogues, IRE1α and IRE1β, whose roles in intestinal physiology are incompletely understood. We examined the individual and cooperative functions of IRE1α and IRE1β in IECs using mice using intestine-specific deletion of Ire1α or germline Ire1β deletion, and subsequently with double deleted Ire1α, Ire1β mice. At baseline, intestine-specific Ire1α deleted mice and mice with germline Ire1β deletion exhibited no morphologic changes in small intestine or colon, but double deleted Ire1α -/- Ire1β -/- mice developed progressive intestinal and colonic injury and tumorigenesis. In contrast to single-deleted IECs, RNA-Seq from Ire1α -/- Ire1β -/- IECs revealed decreased expression of defense-associated mRNAs, together with increased expression of inflammatory and pathogenic mRNAs. Utilizing orthogonal models of intestinal tumorigenesis, reflecting either inflammatory-mutagenic injury (AOM-DSS) or spontaneous polyposis (APC min ), we observed that loss of either intestinal epithelial Ire1α or of Ire1β alone produced a growth advantage, increasing tumor burden. IRE1α mediated splicing of Xbp1 mRNA was maintained following Ire1β deletion but not in double deleted Ire1α -/- Ire1β -/- mice. Increased expression of either Ire1α or Ire1β mRNA was associated with improved survival in patients with colorectal cancer. Taken together our findings suggest IRE1 paralogues utilize essential but distinct mechanisms to safeguard intestinal homeostasis and suppress tumorigenesis.

DOI: https://doi.org/10.1101/2025.05.01.651751
FEBS J. 2025 Jul 14.

Emerging roles for integrated stress response signaling in homeostasis.

Shyama Nandakumar, Lydia Grmai, Deepika Vasudevan.

  Across phyla, organisms have evolved signaling mechanisms to cope with cell-intrinsic and -extrinsic stressors. The integrated stress response (ISR) is a prime example of such a mechanism and has well-defined roles from yeast to humans in dealing with stress burdens imposed by nutrient deprivation, protein misfolding, infectious agents, and oxidative stress. As with many fundamental cellular processes, the complexity of ISR signaling increases with evolutionary complexity. While single-celled organisms have been reported to utilize ISR signaling in the context of stress, multicellular organisms also rely on ISR signaling components for a number of homeostatic functions. The role of ISR signaling in the absence of obvious stressors is less well-studied, though useful insights into this can be extrapolated from prior studies using loss-of-function mutants in model organisms. This review summarizes the known (and inferred) homeostatic roles for ISR signaling components and speculates on cellular functions and principles that might require stress-adaptive mechanisms such as ISR signaling to maintain homeostasis.

Keywords:  ATF4; ISR; homeostasis; stress

DOI:  https://doi.org/10.1111/febs.70166