bims-unfpre 2024-03-10 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–03–10
ten papers selected by
Susan Logue, University of Manitoba

Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum function.
Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer.
IRE1α inhibits osteogenic differentiation of mouse embryonic fibroblasts by limiting Shh signaling.
Molecular mechanism of ATF6 in unfolded protein response and its role in disease.
KTN1 mediated unfolded protein response protects keratinocytes from ionizing radiation-induced DNA damage.
Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation.
FXR controls duodenogastric reflux-induced gastric inflammation through negatively regulating ER stress-associated TNXIP/NLPR3 inflammasome.
eIF2α-mediated integrated stress response links multiple intracellular signaling pathways to reprogram vascular smooth muscle cell fate in carotid artery plaque.
Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress.
Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection.

Mol Biol Cell. 2024 Mar 06. mbcE24010012

Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum function.

Melissa J Mann, Chris Melendez-Suchi, Hannah E Vorndran, Maria Sukhoplyasova, Ashley R Flory, Mary Carson Irvine, Anuradha R Iyer, Christopher J Guerriero, Jeffrey L Brodsky, Linda M Hendershot, Teresa M Buck.

GRP170 (Hyou1) is required for mouse embryonic development, and its ablation in kidney nephrons leads to renal failure. Unlike most chaperones, GRP170 is the lone member of its chaperone family in the ER lumen. However, the cellular requirement for GRP170, which both binds non-native proteins and acts as nucleotide exchange factor for BiP, is poorly understood. Here, we report on the isolation of mouse embryonic fibroblasts obtained from mice in which LoxP sites were engineered in the Hyou1 loci (Hyou1LoxP/LoxP). A doxycycline-regulated Cre recombinase was stably introduced into these cells. Induction of Cre resulted in depletion of Grp170 protein which culminated in cell death. As Grp170 levels fell we observed a portion of BiP fractionating with insoluble material, increased binding of BiP to a client with a concomitant reduction in its turnover, and reduced solubility of an aggregation-prone BiP substrate. Consistent with disrupted BiP functions, we observed reactivation of BiP and induction of the unfolded protein response (UPR) in futile attempts to provide compensatory increases in ER chaperones and folding enzymes. Together, these results provide insights into the cellular consequences of controlled Grp170 loss and provide hypotheses as to why mutations in the Hyou1 locus are linked to human disease.

DOI: https://doi.org/10.1091/mbc.E24-01-0012
J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 71

Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer.

Peng Chen, Amit Sharma, Hans Weiher, Ingo G H Schmidt-Wolf.

  A firm link between endoplasmic reticulum (ER) stress and tumors has been wildly reported. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α), an ER-resident thiol oxidoreductase, is confirmed to be highly upregulated in various cancer types and associated with a significantly worse prognosis. Of importance, under ER stress, the functional interplay of ERO1α/PDI axis plays a pivotal role to orchestrate proper protein folding and other key processes. Multiple lines of evidence propose ERO1α as an attractive potential target for cancer treatment. However, the unavailability of specific inhibitor for ERO1α, its molecular inter-relatedness with closely related paralog ERO1β and the tightly regulated processes with other members of flavoenzyme family of enzymes, raises several concerns about its clinical translation. Herein, we have provided a detailed description of ERO1α in human cancers and its vulnerability towards the aforementioned concerns. Besides, we have discussed a few key considerations that may improve our understanding about ERO1α in tumors.

Keywords:  Cancer; ER stress; ERO1α; Immune escape; Inhibitor; PDI; Prognosis

DOI:  https://doi.org/10.1186/s13046-024-02990-4
Oral Dis. 2024 Mar 04.

IRE1α inhibits osteogenic differentiation of mouse embryonic fibroblasts by limiting Shh signaling.

Zhixiang Zhang, Xuan Zhang, Xiangzhen Wei, Chengbo Yu, Li Xiao, Jianmiao Liu, Yong Liu, Yingguang Cao, Ke Song.

   OBJECTIVES: This study aimed to investigate the effect of endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) on the sonic hedgehog N-terminus (N-Shh)-enhanced-osteogenic differentiation process in mouse embryonic fibroblasts (MEFs).
MATERIALS AND METHODS: Osteogenesis of MEFs was observed by alkaline phosphatase (ALP) staining, alizarin red staining, and Von Kossa staining assays. Activation of unfolded protein response and Shh signaling were examined using real-time quantitative PCR and western blot assays. IRE1α-deficient MEFs were used to explore the effect of IRE1α on N-Shh-driven osteogenesis.
RESULTS: N-Shh increased ALP activity, matrix mineralization, and the expression of Alp and Col-I in MEFs under osteogenic conditions; notably, this was reversed when combined with the ER stress activator Tm treatment. Interestingly, the administration of N-Shh decreased the expression of IRE1α. Abrogation of IRE1α increased the expression of Shh pathway factors in osteogenesis-induced MEFs, contributing to the osteogenic effect of N-Shh. Moreover, IRE1α-deficient MEFs exhibited elevated levels of osteogenic markers.
CONCLUSIONS: Our findings suggest that the IRE1α-mediated unfolded protein response may alleviate the ossification of MEFs by attenuating Shh signaling. Our research has identified a strategy to inhibit excessive ossification, which may have clinical significance in preventing temporomandibular joint bony ankylosis.

Keywords:  ER stress; IRE1α; mouse embryonic fibroblasts; osteogenesis; sonic hedgehog

DOI:  https://doi.org/10.1111/odi.14919
Heliyon. 2024 Mar 15. 10(5): e25937

Molecular mechanism of ATF6 in unfolded protein response and its role in disease.

Yingying Lei, Hong Yu, Shaoxue Ding, Hui Liu, Chunyan Liu, Rong Fu.

  Activating transcription factor 6 (ATF6), an important signaling molecule in unfolded protein response (UPR), plays a role in the pathogenesis of several diseases, including diseases such as congenital retinal disease, liver fibrosis and ankylosing spondylitis. After endoplasmic reticulum stress (ERS), ATF6 is activated after separation from binding immunoglobulin protein (GRP78/BiP) in the endoplasmic reticulum (ER) and transported to the Golgi apparatus to be hydrolyzed by site 1 and site 2 proteases into ATF6 fragments, which localize to the nucleus and regulate the transcription and expression of ERS-related genes. In these diseases, ERS leads to the activation of UPR, which ultimately lead to the occurrence and development of diseases by regulating the physiological state of cells through the ATF6 signaling pathway. Here, we discuss the evidence for the pathogenic importance of ATF6 signaling in different diseases and discuss preclinical results.

Keywords:  Activating transcription factor 6 (ATF6); Endoplasmic reticulum stress (ERS); Proteostasis; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.heliyon.2024.e25937
J Dermatol Sci. 2024 Feb 24. pii: S0923-1811(24)00029-X. [Epub ahead of print]

KTN1 mediated unfolded protein response protects keratinocytes from ionizing radiation-induced DNA damage.

Xinli Niu, Yi Shen, Yunhan Wen, Xing Mi, Jing Xie, Ying Zhang, Zhenhua Ding.

   BACKGROUND: The unfolded protein response (UPR) is one of the cytoprotective mechanisms against various stresses and essential for the normal function of skin. Skin injury caused by ionizing radiation (IR) is a common side effect of radiotherapy and it is unclear how UPR affects IR-induced skin injury.
OBJECTIVES: To verify the effect of UPR on IR-induced DNA damage in keratinocytes and the relation between an endoplasmic reticulum (ER) protein KTN1 and UPR.
METHODS: All experiments were performed on keratinocytes models: HaCaT and HEK-A. ER lumen and the expression levels of KTN1 and UPR pathway proteins (PERK, IRE1α and ATF6) were examined by transmission electron microscopy and immunoblotting, respectively. 4-PBA, an UPR inhibitor, was used to detected its effects on DNA damage and cell proliferation. Subsequently, the effects of KTN1 deletion on UPR, DNA damage and cell proliferation after IR were detected. Tunicamycin was used to reactivate UPR and then we examined its effects on DNA damage.
RESULTS: UPR was activated by IR in keratinocytes. Inhibition of UPR aggravated DNA damage and suppressed cell proliferation after IR. KTN1 expression was upregulated by IR and KTN1 depletion reduced ER expansion and the expression of UPR-related proteins. Moreover, KTN1 depletion aggravated DNA damage and suppressed cell proliferation after IR could reversed by reactivation of UPR.
CONCLUSION: KTN1 deletion aggravates IR-induced keratinocyte DNA damage via inhibiting UPR. Our findings provide new insights into the mechanisms of keratinocytes in response to IR-induced damage.

Keywords:  DNA damage; Ionizing radiation; KTN1; Keratinocyte; Unfolded protein response

DOI:  https://doi.org/10.1016/j.jdermsci.2024.02.006
Toxicol Appl Pharmacol. 2024 Mar 02. pii: S0041-008X(24)00081-4. [Epub ahead of print]484 116883

Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation.

Yulian Yang, Zhongzheng He, Shuangchan Wu.

   BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) reduces the overall quality of life and leads to interruption of chemotherapy. Ursolic acid, a triterpenoid naturally which presents in fruit peels and in many herbs and spices, can function as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, and has been widely used as an herbal medicine with a wide spectrum of pharmacological activities, including anti-cancer, anti-inflammatory and neuroprotective effect.
METHODS: We used a phenotypic drug screening approach to identify ursolic acid as a potential neuroprotective drug in vitro and in vivo and carried out additional biochemical experiments to identify its mechanism of action.
RESULTS: Our study demonstrated that ursolic acid reduced neurotoxicity and cell apoptosis induced by pacilitaxel, resulting in an improvement of CIPN. Moreover, we explored the potential mechanisms of ursolic acid on CIPN. As a result, ursolic acid inhibited CHOP (C/EBP Homologous Protein) expression, indicating the endoplasmic reticulum (ER) stress suppression, and regulating CHOP related apoptosis regulator (the Bcl2 family) to reverse pacilitaxel induced apoptosis. Moreover, we showed that the therapeutic effect of ursolic acid on the pacilitaxel-induced peripheral neuropathy is PPARγ dependent.
CONCLUSIONS: Taken together, the present study suggests ursolic acid has potential as a new PPARγ agonist targeting ER stress-related apoptotic pathways to ameliorate pacilitaxel-induced peripheral neuropathic pain and nerve injury, providing new clinical therapeutic method for CIPN.

Keywords:  Chemotherapy-induced peripheral neuropathy; ER Stress; PPARγ; Paclitaxel; Ursolic acid

DOI:  https://doi.org/10.1016/j.taap.2024.116883
iScience. 2024 Mar 15. 27(3): 109118

FXR controls duodenogastric reflux-induced gastric inflammation through negatively regulating ER stress-associated TNXIP/NLPR3 inflammasome.

Junhui Yu, Chenye Zhao, Pengwei Zhao, Mingchao Mu, Xiaopeng Li, Jianbao Zheng, Xuejun Sun.

  Duodenogastric reflux (DGR) is closely associated with gastric inflammation and tumorigenesis; however, the precise mechanism is unclear. Hence, we aim to clarify this molecular mechanism and design an effective therapeutic strategy based on it. The present study found that DGR induced TXNIP/NLRP3 inflammasome activation and triggered pyroptosis in gastric mucosa in vitro and in vivo, in which endoplasmic reticulum (ER) stress via PERK/eIF2α/CHOP signaling was involved. Mechanistically, farnesoid X receptor (FXR) antagonized the DGR-induced PERK/eIF2α/CHOP pathway and reduced TXNIP and NLRP3 expression. Moreover, FXR suppressed NLRP3 inflammasome activation by physically interacting with NLRP3 and caspase-1. Administration of the FXR agonist OCA protected the gastric mucosa from DGR-induced barrier disruption and mucosal inflammation. In conclusion, our study demonstrates the involvement of TXNIP/NLRP3 inflammasome-mediated pyroptosis in DGR-induced gastric inflammation. FXR antagonizes gastric barrier disruption and mucosal inflammation induced by DGR. Restoration of FXR activity may be a therapeutic strategy for DGR-associated gastric tumorigenesis.

Keywords:  Cell Biology; Immunology; Molecular Biology

DOI:  https://doi.org/10.1016/j.isci.2024.109118
Heliyon. 2024 Mar 15. 10(5): e26904

eIF2α-mediated integrated stress response links multiple intracellular signaling pathways to reprogram vascular smooth muscle cell fate in carotid artery plaque.

Jichang Luo, Xiao Zhang, Wenjing Li, Tao Wang, Shengyan Cui, Tianhua Li, Yilin Wang, Wenlong Xu, Yan Ma, Bin Yang, Yumin Luo, Ge Yang, Ran Xu, Liqun Jiao.

   Background: Carotid arterial atherosclerotic stenosis is a well-recognized pathological basis of ischemic stroke; however, its underlying molecular mechanisms remain unknown. Vascular smooth muscle cells (VSMCs) play fundamental roles in the initiation and progression of atherosclerosis. Organelle dynamics have been reported to affect atherosclerosis development. However, the association between organelle dynamics and various cellular stresses in atherosclerotic progression remain ambiguous.
Methods: In this study, we conducted transcriptomics and bioinformatics analyses of stable and vulnerable carotid plaques. Primary VSMCs were isolated from carotid plaques and subjected to histopathological staining to determine their expression profiles. Endoplasmic reticulum (ER), mitochondria, and lysosome dynamics were observed in primary VSMCs and VSMC cell lines using live-cell imaging. Moreover, the mechanisms underlying disordered organelle dynamics were investigated using comprehensive biological approaches.
Results: ER whorls, a representative structural change under ER stress, are prominent dynamic reconstructions of VSMCs between vulnerable and stable plaques, followed by fragmented mitochondria and enlarged lysosomes, suggesting mitochondrial stress and lysosomal defects, respectively. Induction of mitochondrial stress alleviated ER stress and autophagy in an eukaryotic translation initiation factor (eIF)-2α-dependent manner. Furthermore, the effects of eIF2α on ER stress, mitochondrial stress, and lysosomal defects were validated using clinical samples.
Conclusion: Our results indicate that morphological and functional changes in VSMC organelles, especially in ER whorls, can be used as reliable biomarkers for atherosclerotic progression. Moreover, eIF2α plays an important role in integrating multiple stress-signaling pathways to determine the behavior and fate of VSMCs.

Keywords:  Carotid artery atherosclerosis; Organelles; Plaque vulnerability; Primary vascular smooth muscle cells; Translation initiation factor 2α

DOI:  https://doi.org/10.1016/j.heliyon.2024.e26904
Nat Commun. 2024 Mar 08. 15(1): 1908

Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress.

Zhe Zhang, Xiang Kai Leng, Yuan Yuan Zhai, Xiao Zhang, Zhi Wei Sun, Jun Ying Xiao, Jun Feng Lu, Kun Liu, Bo Xia, Qi Gao, Miao Jia, Cheng Qi Xu, Yi Na Jiang, Xiao Gang Zhang, Kai Shan Tao, Jiang Wei Wu.

Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.

DOI: https://doi.org/10.1038/s41467-024-46135-9
Front Immunol. 2024 ;15 1332942

Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection.

Bin Yang, Shu Wang, Yanfang Yang, Xukui Li, Fuxun Yu, Tao Wang.

   Background: Breast cancer (BC) is a leading cause of mortality among women, underscoring the urgent need for improved therapeutic predictio. Developing a precise prognostic model is crucial. The role of Endoplasmic Reticulum Stress (ERS) in cancer suggests its potential as a critical factor in BC development and progression, highlighting the importance of precise prognostic models for tailored treatment strategies.
Methods: Through comprehensive analysis of ERS-related gene expression in BC, utilizing both single-cell and bulk sequencing data from varied BC subtypes, we identified eight key ERS-related genes. LASSO regression and machine learning techniques were employed to construct a prognostic model, validated across multiple datasets and compared with existing models for its predictive accuracy.
Results: The developed ERS-model categorizes BC patients into distinct risk groups with significant differences in clinical prognosis, confirmed by robust ROC, DCA, and KM analyses. The model forecasts survival rates with high precision, revealing distinct immune infiltration patterns and treatment responsiveness between risk groups. Notably, we discovered six druggable targets and validated Methotrexate and Gemcitabine as effective agents for high-risk BC treatment, based on their sensitivity profiles and potential for addressing the lack of active targets in BC.
Conclusion: Our study advances BC research by establishing a significant link between ERS and BC prognosis at both the molecular and cellular levels. By stratifying patients into risk-defined groups, we unveil disparities in immune cell infiltration and drug response, guiding personalized treatment. The identification of potential drug targets and therapeutic agents opens new avenues for targeted interventions, promising to enhance outcomes for high-risk BC patients and paving the way for personalized cancer therapy.

Keywords:  breast cancer; endoplasmic reticulum stress; immunotherapy; methotrexate; prognosis

DOI:  https://doi.org/10.3389/fimmu.2024.1332942