bims-unfpre 2024-09-22 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–09–22
nine papers selected by
Susan Logue, University of Manitoba

Structural basis of CDNF interaction with the UPR regulator GRP78.
IRE1α regulates ROS and immune responses after UVB irradiation.
Identification of immune-related endoplasmic reticulum stress genes in proliferative diabetic retinopathy using bioinformatics analysis.
The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
A new perspective on liver diseases: Focusing on the mitochondria-associated endoplasmic reticulum membranes.
Endoplasmic Reticulum Stress and Obesity.
The stability of FKBP9 maintained by BiP is crucial for glioma progression.
ER-phagy restrains inflammatory responses through its receptor UBAC2.
Endoplasmic reticulum-targeted biomimetic nanoparticles induce apoptosis and ferroptosis by regulating endoplasmic reticulum function in colon cancer.

Nat Commun. 2024 Sep 18. 15(1): 8175

Structural basis of CDNF interaction with the UPR regulator GRP78.

Melissa A Graewert, Maria Volkova, Klara Jonasson, Juha A E Määttä, Tobias Gräwert, Samara Mamidi, Natalia Kulesskaya, Johan Evenäs, Richard E Johnsson, Dmitri Svergun, Arnab Bhattacharjee, Henri J Huttunen.

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson's disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway. Subsequent binding studies confirm the obtained structural model of the complex, eventually revealing the interaction site of CDNF and GRP78. Finally, mutating the key residues of CDNF mediating its interaction with GRP78 not only results in impaired binding of CDNF but also abolishes the neuroprotective activity of CDNF-derived peptides in mesencephalic neuron cultures. These results suggest that the molecular interaction with GRP78 mediates the neuroprotective actions of CDNF and provide a structural basis for development of next generation CDNF-based therapeutic compounds against neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41467-024-52478-0
Redox Exp Med. 2024 Jan;pii: e230030. [Epub ahead of print]2024(1):

IRE1α regulates ROS and immune responses after UVB irradiation.

Jeongin Son, Jacob T Bailey, Stephen Worrell, Adam B Glick.

   Objective: UV irradiation of the skin induces photo damage and generates cytotoxic intracellular reactive oxygen species (ROS), activating the unfolded protein response (UPR) to adapt or reduce these UVB-mediated damages. This study was designed to understand the role of the UPR mediator IRE1α in the antioxidant response following UVB irradiation of mouse skin and keratinocytes.
Methods: We used mice with an epidermal deletion of IRE1α and primary mouse keratinocytes to examine effects of UV on different parameters of the antioxidant response in the presence and absence of functional IRE1α.
Results: In the absence of IRE1α, PERK activity and protein levels are significantly compromised following UVB irradiation. Additionally, the loss of IRE1α suppressed phosphorylation of the PERK target, nuclear factor erythroid-2-related factor 2 (NRF2), and NRF2-dependent antioxidant gene expression after UVB irradiation. Interestingly, IRE1α-deficient keratinocytes exhibit elevated basal ROS levels, while a robust ROS induction upon UVB exposure is abolished. Because UVB-induced ROS plays an essential role in regulating skin inflammation, we analyzed recruited immune cell populations and the expression of pro-inflammatory cytokines, Il-6 and Tnfα in mice with epidermally-targeted deletion of Ire1α. Following UVB irradiation, there was significantly less recruitment of neutrophils and leukocytes and reduced expression of pro-inflammatory cytokine genes in the skin of mice lacking IRE1α. Furthermore, keratinocyte proliferation was also significantly reduced after chronic UVB exposure in the skin of these mice.
Conclusions: Collectively, our findings indicate that IRE1α is essential for basal and UVB-induced oxidative stress response, UV-induced skin immune responses, and keratinocyte proliferation.
Significance: These findings shed new light on the protective function of IRE1α in the response to UV. IRE1α plays an important role in the regulation of ROS, PERK stability, and antioxidant gene expression in response to UVB in mouse keratinocytes and epidermis.

Keywords:  ER stress; IRE1α; ROS; Skin; UVB; Unfolded Protein Response; cytokines

DOI:  https://doi.org/10.1530/rem-23-0030
Front Endocrinol (Lausanne). 2024 ;15 1341206

Identification of immune-related endoplasmic reticulum stress genes in proliferative diabetic retinopathy using bioinformatics analysis.

Han Chen, Enguang Chen, Miaomiao Liu, Jianhui Wang, Jiawei Yin, Peiquan Zhao, Yu Xu.

   Background: Proliferative diabetic retinopathy (PDR) is a severe complication of diabetes, and understanding its molecular mechanisms is crucial. Endoplasmic reticulum (ER) stress has been implicated in various diseases, including diabetic complications. This study aims to elucidate ER stress-related biomarkers in PDR, providing insights into the underlying molecular pathways.
Methods: We analyzed two independent PDR datasets, GSE102485 and GSE60436. The GSE102485 dataset (22 PDR and 3 normal samples) was the primary dataset for comprehensive analyses, including differential expression, functional enrichment, PPI network construction, immune cell infiltration, and drug prediction. The GSE60436 dataset (6 PDR and 3 normal samples) was used for validation. In vitro experiments using human umbilical vein endothelial cells (HUVECs) in a high-glucose environment were conducted to validate key bioinformatics outcomes. Western blotting assessed protein levels of ER stress markers (TRAM1 and TXNIP).
Results: Differential expression analysis identified 2451 genes, including 328 ER stress-related genes. Functional analysis revealed enrichment in ER stress-related processes and pathways. Hub genes (BCL2, CCL2, IL-1β, TLR4, TNF, TP53) were identified, and immune infiltration analysis showed altered immune cell proportions. Validation in GSE60436 and in vitro confirmed ER stress gene dysregulation. Drug prediction suggested potential small molecules targeting ER stress markers.
Conclusion: This study provides a comprehensive molecular characterization of ER stress in PDR, highlighting altered biological processes, immune changes, and potential therapeutic targets. The identified hub genes and small molecules offer avenues for further investigation and therapy development, enhancing understanding of PDR pathogenesis and aiding targeted intervention creation.

Keywords:  bioinformatics; biomarkers; differentially expressed genes; drug prediction; endoplasmic reticulum stress; proliferative diabetic retinopathy

DOI:  https://doi.org/10.3389/fendo.2024.1341206
Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2400531121

The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.

Xiying Wang, Ji Geng, Suman Rimal, Yuxiu Sui, Jie Pan, Zhenghong Qin, Bingwei Lu.

  It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases.

Keywords:  DRAM1; ER; ER-phagy; calcium homeostasis; lysosome

DOI:  https://doi.org/10.1073/pnas.2400531121
Pharmacol Res. 2024 Sep 14. pii: S1043-6618(24)00354-2. [Epub ahead of print]208 107409

A new perspective on liver diseases: Focusing on the mitochondria-associated endoplasmic reticulum membranes.

Mengyu Guo, Runping Liu, Fukun Zhang, Jiaorong Qu, Yun Yang, Xiaojiaoyang Li.

  The pathogenesis of liver diseases is multifaceted and intricate, posing a persistent global public health challenge with limited therapeutic options. Therefore, further research into liver diseases is imperative for better comprehension and advancement in treatment strategies. Numerous studies have confirmed the endoplasmic reticulum (ER) and mitochondria as key organelles driving liver diseases. Notably, the mitochondrial-associated ER membranes (MAMs) establish a physical and functional connection between the ER and mitochondria, highlighting the importance of inter-organelle communication in maintaining their functional homeostasis. This review delves into the intricate architecture and regulative mechanism of the integrated MAM that facilitate the physiological transfer of signals and substances between organelles. Additionally, we also provide a detailed overview regarding the varied pathogenic roles of malfunctioning MAM in liver diseases, focusing on its involvement in the progression of ER stress and mitochondrial dysfunction, the regulation of mitochondrial dynamics and Ca2+ transfer, as well as the disruption of lipid and glucose homeostasis. Furthermore, the current challenges and prospects associated with MAM in liver disease research are thoroughly discussed. In conclusion, elucidating the specific structure and function of MAM in different liver diseases may pave the way for novel therapeutic strategies.

Keywords:  Calcium homeostasis; ER stress; Liver diseases; Mitochondria-associated endoplasmic reticulum membranes; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.phrs.2024.107409
Adv Exp Med Biol. 2024 ;1460 373-390

Endoplasmic Reticulum Stress and Obesity.

Erkan Yilmaz.

  In recent years, the world has seen an alarming increase in obesity and is closely associated with insulin resistance, which is a state of low-grade inflammation, the latter characterized by elevated levels of proinflammatory cytokines in blood and tissues. A shift in energy balance alters systemic metabolic regulation and the important role that chronic inflammation, endoplasmic reticulum (ER) dysfunction, and activation of the unfolded protein response (UPR) plays in this process.Why obesity is so closely associated with insulin resistance and inflammation is not understood well. This suggests that there are probably many causes for obesity-related insulin resistance and inflammation. One of the faulty mechanisms is protein homeostasis, protein quality control system included protein folding, chaperone activity, and ER-associated degradation leading to endoplasmic reticulum (ER) stress.The ER is a vast membranous network responsible for the trafficking of a wide range of proteins and plays a central role in integrating multiple metabolic signals critical in cellular homeostasis. Conditions that may trigger unfolded protein response activation include increased protein synthesis, the presence of mutant or misfolded proteins, inhibition of protein glycosylation, imbalance of ER calcium levels, glucose and energy deprivation, hypoxia, pathogens, or pathogen-associated components and toxins. Thus, characterizing the mechanisms contributing to obesity and identifying potential targets for its prevention and treatment will have a great impact on the control of associated conditions, particularly T2D.

Keywords:  Autophagy; Endoplasmic reticulum stress; Lipotoxicity; Obesity; Type 2 diabetes

DOI:  https://doi.org/10.1007/978-3-031-63657-8_13
Genes Dis. 2024 Nov;11(6): 101123

The stability of FKBP9 maintained by BiP is crucial for glioma progression.

Shirong Li, Wangxiao Xia, Bin Sun, Weiyan Peng, Dong Yang, Jing Gao, Shuai He, Hua Yang, Yongjie Zhu, Hu Zhou, Tingxiu Xiang, Qingpeng Kong, Xudong Zhao.

  FK506-binding protein 9 (FKBP9) is involved in tumor malignancy by resistance to endoplasmic reticulum (ER) stress, and the up-regulation of FKBP9 is associated with patients' poor prognosis. The current knowledge of the molecular mechanisms is still limited. One previous study showed that FKBP9 could confer glioblastoma cell resistance to ER stress through ASK1-p38 signaling. However, the upstream regulatory mechanism of FKBP9 expression is still indistinct. In this study, we identified the FKBP9 binding proteins using co-immunoprecipitation followed by mass spectrometry. Results showed that FKBP9 interacted with the binding immunoglobulin protein (BiP). BiP bound directly to FKBP9 with high affinity. BiP prolonged the half-life of the FKBP9 protein and stabilized the FKBP9 protein. BiP and FKBP9 protein levels were positively correlated in patients with glioma, and patients with high expression of BiP and FKBP9 showed a worse prognosis. Further studies showed that FKBP9 knockout in genetically engineered mice inhibited intracranial glioblastoma formation and prolonged survival by decreasing cellular proliferation and ER stress-induced CHOP-related apoptosis. Moreover, normal cells may depend less on FKBP9, as shown by the absence of apoptosis upon FKBP9 knockdown in a non-transformed human cell line and overall normal development in homozygous knockout mice. These findings suggest an important role of BiP-regulated FKBP9-associated signaling in glioma progression and the BiP-FKBP9 axis may be a potential therapeutic target for glioma.

Keywords:  BiP; Endoplasmic reticulum stress; FKBP9; Glioma; Knockout mice

DOI:  https://doi.org/10.1016/j.gendis.2023.101123
EMBO J. 2024 Sep 16.

ER-phagy restrains inflammatory responses through its receptor UBAC2.

Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, Shouheng Jin.

  ER-phagy, a selective form of autophagic degradation of endoplasmic reticulum (ER) fragments, plays an essential role in governing ER homeostasis. Dysregulation of ER-phagy is associated with the unfolded protein response (UPR), which is a major clue for evoking inflammatory diseases. However, the molecular mechanism underpinning the connection between ER-phagy and disease remains poorly defined. Here, we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy, while at the same time being a negative regulator of inflammatory responses. UBAC2 harbors a canonical LC3-interacting region (LIR) in its cytoplasmic domain, which binds to autophagosomal GABARAP. Upon ER-stress or autophagy activation, microtubule affinity-regulating kinase 2 (MARK2) phosphorylates UBAC2 at serine (S) 223, promoting its dimerization. Dimerized UBAC2 interacts more strongly with GABARAP, thus facilitating selective degradation of the ER. Moreover, by affecting ER-phagy, UBAC2 restrains inflammatory responses and acute ulcerative colitis (UC) in mice. Our findings indicate that ER-phagy directed by a MARK2-UBAC2 axis may provide targets for the treatment of inflammatory disease.

Keywords:  Colitis; ER-phagy; Inflammatory Responses; MARK2; UBAC2

DOI:  https://doi.org/10.1038/s44318-024-00232-z
J Control Release. 2024 Sep 18. pii: S0168-3659(24)00628-X. [Epub ahead of print]375 422-437

Endoplasmic reticulum-targeted biomimetic nanoparticles induce apoptosis and ferroptosis by regulating endoplasmic reticulum function in colon cancer.

Hongxin Tan, Ziqi Shen, Xiaohua Wang, Sicheng Shu, Jie Deng, Li Lu, Ziyan Fan, Danni Hu, Pu Cheng, Xi Cao, Qi Huang.

  Colorectal cancer (CRC) is a major threat to human health, as it is one of the most common malignancies with a high incidence and mortality rate. The cancer cell membrane (CCM) has significant potential in targeted tumor drug delivery due to its membrane antigen-mediated homologous targeting ability. The endoplasmic reticulum (ER) in cancer cells plays a crucial role in apoptosis and ferroptosis. In this study, we developed an ER-targeted peptide-modified CCM-biomimetic nanoparticle-delivered lovastatin (LOV) nanomedicine delivery system (EMPP-LOV) for cancer treatment. Both in vitro and in vivo experiments demonstrated that EMPP could effectively target cancer cells and localize within the ER. EMPP-LOV modulated ER function to promote apoptosis and ferroptosis in tumor cells. Furthermore, synergistic antitumor efficacy was observed in both in vitro and in vivo models. EMPP-LOV induced apoptosis in CRC cells by over-activating endoplasmic reticulum stress and promoted ferroptosis by inhibiting the mevalonate pathway, leading to synergistic tumor growth inhibition with minimal toxicity to major organs. Overall, the EMPP-LOV delivery system, with its subcellular targeting capability within tumor cells, presents a promising therapeutic platform for CRC treatment.

Keywords:  Biomimetic nanoparticles; Cell apoptosis; Colorectal cancer; Endoplasmic reticulum-targeted; Ferroptosis

DOI:  https://doi.org/10.1016/j.jconrel.2024.09.018