bims-unfpre 2024-01-21 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024‒01‒21
eleven papers selected by
Susan Logue, University of Manitoba

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis.
Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice.
MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response.
miR-217 regulates normal and tumor cell fate following induction of Endoplasmic Reticulum Stress.
SIRT1 regulates endoplasmic reticulum stress-related organ damage.
RBM25 regulates hypoxic cardiomyocyte apoptosis through CHOP-associated endoplasmic reticulum stress.
Gene module reconstruction elucidates cellular differentiation processes and the regulatory logic of specialized secretion.
Quantitative proteomic analyses uncover regulatory roles of Nrf2 in human endothelial cells.
Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress.
NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
Unveiling a differential metabolite modulation of sorghum varieties under increasing tunicamycin-induced endoplasmic reticulum stress.

Cell Death Dis. 2024 Jan 17. 15(1): 63

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis.

Haijiao Jin, Yuanting Yang, Xuying Zhu, Yin Zhou, Yao Xu, Jialin Li, Chaojun Qi, Xinghua Shao, Jingkui Wu, Shan Wu, Hong Cai, Leyi Gu, Shan Mou, Zhaohui Ni, Shu Li, Qisheng Lin.

Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI-induced by contrast media, ischemia-reperfusion injury, cisplatin, and folic acid-to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1-UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

DOI: https://doi.org/10.1038/s41419-024-06449-4
J Biol Chem. 2024 Jan 16. pii: S0021-9258(24)00031-0. [Epub ahead of print] 105655

Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice.

Tamana R Yousof, Celeste C Bouchard, Mihnea Alb, Edward G Lynn, Sárka Lhoták, Hua Jiang, Melissa MacDonald, Hui Li, Jae H Byun, Yumna Makda, Maria Athanasopoulos, Kenneth N Maclean, Nathan Cherrington, Asghar Naqvi, Suleiman Igdoura, Joan C Krepinsky, Gregory R Steinberg, Richard C Austin.

  Endoplasmic reticulum (ER) stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease (NAFLD). Deficiency of the ER stress response TDAG51 gene (TDAG51-/-) in mice promotes the development of high fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance (IR). However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease, compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in wild type, TDAG51-/- and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51-/- mice and in ob/ob mice. TDAG51-/- mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD fed TDAG51-/- mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP treated TDAG51-/- mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and -2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels may represent a viable therapeutic approach for the treatment of obesity and IR associated with NAFLD.

Keywords:  hepatocyte; insulin resistance; lipid metabolism; liver; obesity; triglyceride

DOI:  https://doi.org/10.1016/j.jbc.2024.105655
EMBO J. 2024 Jan 18.

MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response.

Wenjuan Ma, Shah Adil Ishtiyaq Ahmad, Michihiro Hashimoto, Ahad Khalilnezhad, Miho Kataoka, Yuichiro Arima, Yosuke Tanaka, Shigeru Yanagi, Terumasa Umemoto, Toshio Suda.

  Hematopoietic stem cell (HSC) divisional fate and function are determined by cellular metabolism, yet the contribution of specific cellular organelles and metabolic pathways to blood maintenance and stress-induced responses in the bone marrow remains poorly understood. The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 (encoded by the Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and to promote cell survival. Here, we investigated the functional involvement of MITOL in HSC maintenance by generating MX1-cre inducible Mitol knockout mice. MITOL deletion in the bone marrow resulted in HSC exhaustion and impairment of bone marrow reconstitution capability in vivo. Interestingly, MITOL loss did not induce major mitochondrial dysfunction in hematopoietic stem and progenitor cells. In contrast, MITOL deletion induced prolonged ER stress in HSCs, which triggered cellular apoptosis regulated by IRE1α. In line, dampening of ER stress signaling by IRE1α inihibitor KIRA6 partially rescued apoptosis of long-term-reconstituting HSC. In summary, our observations indicate that MITOL is a principal regulator of hematopoietic homeostasis and protects blood stem cells from cell death through its function in ER stress signaling.

Keywords:  Apoptosis; Cell Cycle; ER Stress Response; IRE1; MITOL

DOI:  https://doi.org/10.1038/s44318-024-00029-0
Mol Cancer Res. 2024 Jan 18.

miR-217 regulates normal and tumor cell fate following induction of Endoplasmic Reticulum Stress.

Neekkan Dey, Constantinos Koumenis, Davide Ruggero, Serge Y Fuchs, J Alan Diehl.

Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. Limits in nutrient availability typically trigger growth arrest and/or apoptosis to prevent cellular expansion. However, tumor cells frequently co-opt cellular survival pathways thereby favoring cell survival under this environmental stress. The Unfolded Protein Response (UPR) pathway is typically engaged by tumor cells to favor adaptation to stress. PERK, an endoplasmic reticulum (ER) protein kinase and UPR effector is activated in tumor cells and contributes tumor cell adaptation by limiting protein translation and balancing redox stress. PERK also induces micro-RNAs that contribute to tumor adaptation. miR-211 and miR-216b were previously identified as a PERK-ATF4 regulated micro-RNAs that regulate cell survival. We have identified another PERK responsive miRNA, miR-217, with increased expression under prolonged ER stress. Key targets of miR-217 are identified as TRPM1, the host gene for miR-211 and EZH2. Evidence is provided that miR-217 expression is essential for the rapid loss of miR-211 in prolonged ER stress and provides a functional link for determining whether cells adapt to stress or commit to apoptosis. Implications: PERK-dependent induction of miR-217 limits accumulation and function of the pro-survival micro-RNA, miR-211, to establish cell fate and promote cell commitment to apoptosis.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0676
Acta Histochem. 2024 Jan 17. pii: S0065-1281(24)00002-3. [Epub ahead of print]126(1): 152134

SIRT1 regulates endoplasmic reticulum stress-related organ damage.

He Hu, Weichao Xu, Yan Li, Zhicheng Wang, Siyue Wang, Yansheng Liu, Minan Bai, Yingying Lou, Qian Yang.

  Endoplasmic reticulum (ER) stress plays a key role in the pathogenesis of several organ damages. Studies show that excessive ER stress (ERS) can destroy cellular homeostasis, causing cell damage and physiological dysfunction in various organs. In recent years, Sirtuin1 (SIRT1) has become a research hotspot on ERS. Increasing evidence suggests that SIRT1 plays a positive role in various ERS-induced organ damage via multiple mechanisms, including inhibiting cellular apoptosis and promoting autophagy. SIRT1 can also alleviate liver, heart, lung, kidney, and intestinal damage by inhibiting ERS. We discuss the possible mechanism of SIRT1, explore potential therapeutic targets of diseases, and provide a theoretical basis for treating ERS-related diseases.

Keywords:  Endoplasmic reticulum stress; Organ damage; Silencing of the regulatory protein 1

DOI:  https://doi.org/10.1016/j.acthis.2024.152134
Cell Stress Chaperones. 2023 Nov;pii: S1355-8145(24)00022-1. [Epub ahead of print]28(6): 861-876

RBM25 regulates hypoxic cardiomyocyte apoptosis through CHOP-associated endoplasmic reticulum stress.

Ziwei Zhu, Jie Pu, Yongnan Li, Jianshu Chen, Hong Ding, Anyu Zhou, XiaoWei Zhang.

  Ischemic heart failure (HF) is one of the leading causes of global morbidity and mortality; blocking the apoptotic cascade could help improve adverse outcomes of it. RNA-binding motif protein 25 (RBM25) is an RNA-binding protein related to apoptosis; however, its role remains unknown in ischemic HF. The main purpose of this study is to explore the mechanism of RBM25 in ischemic HF. Establishing an ischemic HF model and oxygen-glucose deprivation (OGD) model. ELISA was performed to evaluate the BNP level in the ischemic HF model. Echocardiography and histological analysis were performed to assess cardiac function and infarct size. Proteins were quantitatively and locationally analyzed by western blotting and immunofluorescence. The morphological changes of endoplasmic reticulum (ER) were observed with ER-tracker. Cardiac function and myocardial injury were observed in ischemic HF rats. RBM25 was elevated in cardiomyocytes of hypoxia injury hearts and localized in nucleus both in vitro and in vivo. In addition, cell apoptosis was significantly increased when overexpressed RBM25. Moreover, ER stress stimulated upregulation of RBM25 and promoted cell apoptosis through the CHOP related pathway. Finally, inhibiting the expression of RBM25 could ameliorate the apoptosis and improve cardiac function through blocking the activation of CHOP signaling pathway. RBM25 is significantly upregulated in ischemic HF rat heart and OGD model, which leads to apoptosis by modulating the ER stress through CHOP pathway. Knockdown of RBM25 could reverse apoptosis-mediated cardiac dysfunction. RBM25 may be a promising target for the treatment of ischemic HF.

Keywords:  Apoptosis; Endoplasmic reticulum stress; Ischemic heart failure; Myocardial infarction; RBM25

DOI:  https://doi.org/10.1007/s12192-023-01380-7
bioRxiv. 2023 Dec 29. pii: 2023.12.29.573643. [Epub ahead of print]

Gene module reconstruction elucidates cellular differentiation processes and the regulatory logic of specialized secretion.

Yiqun Wang, Jialin Liu, Lucia Y Du, Jannik L Wyss, Jeffrey A Farrell, Alexander F Schier.

During differentiation, cells become structurally and functionally specialized, but comprehensive views of the underlying remodeling processes are elusive. Here, we leverage scRNA-seq developmental trajectories to reconstruct differentiation using two secretory tissues as a model system: the zebrafish notochord and hatching gland. First, we present an approach to integrate expression and functional similarities for gene module identification, revealing dozens of gene modules representing known and newly associated differentiation processes and their temporal ordering. Second, we focused on the unfolded protein response (UPR) transducer module to study how general versus cell-type specific secretory functions are regulated. By profiling loss- and gain-of-function embryos, we found that the UPR transcription factors creb3l1, creb3l2, and xbp1 are master regulators of a general secretion program. creb3l1/creb3l2 additionally activate an extracellular matrix secretion program, while xbp1 partners with bhlha15 to activate a gland-specific secretion program. Our study offers a multi-source integrated approach for functional gene module identification and illustrates how transcription factors confer general and specialized cellular functions.

DOI: https://doi.org/10.1101/2023.12.29.573643
Cell Stress Chaperones. 2023 Nov;pii: S1355-8145(24)00008-7. [Epub ahead of print]28(6): 731-747

Quantitative proteomic analyses uncover regulatory roles of Nrf2 in human endothelial cells.

Karan Naresh Amin, Palanichamy Rajaguru, Takayoshi Suzuki, Koustav Sarkar, Kumar Ganesan, Kunka Mohanram Ramkumar.

  Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator, is the predominant factor in modulating oxidative stress and other cellular signaling responses. Studies from our lab and others highlighted that activation of the Nrf2 pathway by small molecules improves endothelial function by suppressing oxidative and endoplasmic reticulum (ER) stress. However, the exact mechanisms by which Nrf2 elicits these effects are unknown. In the present study, we developed CRISPR/Cas9-mediated Nrf2 knocked-out human endothelial cells, and proteomic signature was studied using LC-MS/MS. We identified 723 unique proteins, of which 361 proteins were found to be differentially regulated and further screened in the Nrf2ome online database, where we identified a highly interconnected signaling network in which 70 proteins directly interact with Nrf2. These proteins were found to regulate some key cellular and metabolic processes in the regulation actin cytoskeleton, ER stress, angiogenesis, inflammation, Hippo signaling pathway, and epidermal growth factor/fibroblast growth factor (EGF/FGF) signaling pathway. Our findings suggest the role of Nrf2 in maintaining endothelium integrity and its relationship with the crucial cellular processes which help develop novel therapeutics against endothelial dysfunction and its associated complications.

Keywords:  Endothelial cells; Endothelial dysfunction; Nrf2ome; Nuclear factor erythroid 2-related factor

DOI:  https://doi.org/10.1007/s12192-023-01366-5
Cell Death Discov. 2024 Jan 18. 10(1): 36

Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress.

Shixin Liu, Pingshan Yang, Lu Wang, Xiaofang Zou, Dongdong Zhang, Wenyou Chen, Chuang Hu, Duqing Xiao, Hongzheng Ren, Hao Zhang, Songwang Cai.

Chemoresistance poses a significant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-activated kinase 4 (PAK4) has been implicated in NSCLC progression by invasion and migration. However, the involvement of PAK4 in cisplatin resistance is not clear. Here, we presented a comprehensive investigation into the involvement of PAK4 in cisplatin resistance within NSCLC. Our study revealed enhanced PAK4 expression in both cisplatin-resistant NSCLC tumors and cell lines. Notably, PAK4 silencing led to a remarkable enhancement in the chemosensitivity of cisplatin-resistant NSCLC cells. Cisplatin evoked endoplasmic reticulum stress in NSCLC. Furthermore, inhibition of PAK4 demonstrated the potential to sensitize resistant tumor cells through modulating endoplasmic reticulum stress. Mechanistically, we unveiled that the suppression of the MEK1-GRP78 signaling pathway results in the sensitization of NSCLC cells to cisplatin after PAK4 knockdown. Our findings establish PAK4 as a promising therapeutic target for addressing chemoresistance in NSCLC, potentially opening new avenues for enhancing treatment efficacy and patient outcomes.

DOI: https://doi.org/10.1038/s41420-024-01798-7
Nat Commun. 2024 Jan 16. 15(1): 546

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.

Liang Yang, Zifeng Ruan, Xiaobing Lin, Hao Wang, Yanmin Xin, Haite Tang, Zhijuan Hu, Yunhao Zhou, Yi Wu, Junwei Wang, Dajiang Qin, Gang Lu, Kerry M Loomes, Wai-Yee Chan, Xingguo Liu.

Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.

DOI: https://doi.org/10.1038/s41467-024-44808-z
Cell Stress Chaperones. 2023 Nov;pii: S1355-8145(24)00024-5. [Epub ahead of print]28(6): 889-907

Unveiling a differential metabolite modulation of sorghum varieties under increasing tunicamycin-induced endoplasmic reticulum stress.

Francisco Lucas Pacheco Cavalcante, Sávio Justino da Silva, Lineker de Sousa Lopes, Stelamaris de Oliveira Paula-Marinho, Maria Izabel Florindo Guedes, Enéas Gomes-Filho, Humberto Henrique de Carvalho.

  Plants trigger endoplasmic reticulum (ER) pathways to survive stresses, but the assistance of ER in plant tolerance still needs to be explored. Thus, we selected sensitive and tolerant contrasting abiotic stress sorghum varieties to test if they present a degree of tolerance to ER stress. Accordingly, this work evaluated crescent concentrations of tunicamycin (TM µg mL-1): control (0), lower (0.5), mild (1.5), and higher (2.5) on the initial establishment of sorghum seedlings CSF18 and CSF20. ER stress promoted growth and metabolism reductions, mainly in CSF18, from mild to higher TM. The lowest TM increased SbBiP and SbPDI chaperones, as well as SbbZIP60, and SbbIRE1 gene expressions, but mild and higher TM decreased it. However, CSF20 exhibited higher levels of SbBiP and SbbIRE1 transcripts. It corroborated different metabolic profiles among all TM treatments in CSF18 shoots and similarities between profiles of mild and higher TM in CSF18 roots. Conversely, TM profiles of both shoots and roots of CSF20 overlapped, although it was not complete under low TM treatment. Furthermore, ER stress induced an increase of carbohydrates (dihydroxyacetone in shoots, and cellobiose, maltose, ribose, and sucrose in roots), and organic acids (pyruvic acid in shoots, and butyric and succinic acids in roots) in CSF20, which exhibited a higher degree of ER stress tolerance compared to CSF18 with the root being the most affected plant tissue. Thus, our study provides new insights that may help to understand sorghum tolerance and the ER disturbance as significant contributor for stress adaptation and tolerance engineering.

Keywords:  Cell stress; Chaperones; GC-MS; Metabolic profile; Primary metabolites

DOI:  https://doi.org/10.1007/s12192-023-01382-5