A common approach for fighting tuberculosis and leprosy: controlling endoplasmic reticulum stress in myeloid-derived suppressor cells

Leprosy and tuberculosis are infectious diseases that are caused by bacteria, and both share primary risk factors. Mediators of these diseases are regulated by a heterogeneous immature population of myeloid cells called myeloid-derived suppressor cells (MDSCs) that exhibit immunosuppressive activity against innate and adaptive immunity. During pathological conditions, endoplasmic reticulum (ER) stress occurs in MDSCs, and high levels of ER stress affect MDSC-linked immunosuppressive activity. Investigating the role of ER stress in regulating immunosuppressive functions of MDSCs in leprosy and tuberculosis may lead to new approaches to treating these diseases. Here the authors discuss the immunoregulatory effects of ER stress in MDSCs as well as the possibility of targeting unfolded protein response elements of ER stress to diminish the immunosuppressive activity of MDSCs and reinvigorate diminished adaptive immune system responses that occur in leprosy and tuberculosis.

Exploring the Role of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma through the Mining of the Human Protein Atlas

Biology ◽

10.3390/biology10070640 ◽

2021 ◽

Vol 10 (7) ◽

pp. 640

Author(s):

Nataša Pavlović ◽

Femke Heindryckx

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Predictive Biomarkers ◽

Human Protein ◽

Disease Stage ◽

Unfolded Protein ◽

Human Protein Atlas ◽

Associated Proteins ◽

Endoplasmic reticulum (ER) stress and actors of unfolded protein response (UPR) have emerged as key hallmarks of hepatocarcinogenesis. Numerous reports have shown that the main actors in the UPR pathways are upregulated in HCC and contribute to the different facets of tumor initiation and disease progression. Furthermore, ER-stress inducers and inhibitors have shown success in preclinical HCC models. Despite the mounting evidence of the UPR’s involvement in HCC pathogenesis, it remains unclear how ER-stress components can be used safely and effectively as therapeutic targets or predictive biomarkers for HCC patients. In an effort to add a clinical context to these findings and explore the translational potential of ER-stress in HCC, we performed a systematic overview of UPR-associated proteins as predictive biomarkers in HCC by mining the Human Protein Atlas database. Aside from evaluating the prognostic value of these markers in HCC, we discussed their expression in relation to patient age, sex, ethnicity, disease stage, and tissue localization. We thereby identified 44 UPR-associated proteins as unfavorable prognostic markers in HCC. The expression of these markers was found to be higher in tumors compared to the stroma of the hepatic HCC patient tissues.

Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802254115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5203-E5212 ◽

Cited By ~ 19

Author(s):

Ya-Shiuan Lai ◽

Luciana Renna ◽

John Yarema ◽

Cristina Ruberti ◽

Sheng Yang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Salicylic Acid ◽

Er Stress ◽

Stress Responses ◽

Unfolded Protein ◽

Redox Activation ◽

Genetic Level ◽

The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR.

Therapeutic Role of Sirtuins Targeting Unfolded Protein Response, Coagulation, and Inflammation in Hypoxia-Induced Thrombosis

Frontiers in Physiology ◽

10.3389/fphys.2021.733453 ◽

2021 ◽

Vol 12 ◽

Author(s):

Khan Sadia ◽

Mohammad Zahid Ashraf ◽

Aastha Mishra

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

The Body ◽

Coagulation Cascade ◽

Nuclear Factor ◽

Unfolded Protein ◽

Inflammatory Pathways ◽

Thrombosis remains one of the leading causes of morbidity and mortality across the world. Many pathological milieus in the body resulting from multiple risk factors escort thrombosis. Hypoxic condition is one such risk factor that disturbs the integrity of endothelial cells to cause an imbalance between anticoagulant and procoagulant proteins. Hypoxia generates reactive oxygen species (ROS) and triggers inflammatory pathways to augment the coagulation cascade. Hypoxia in cells also activates unfolded protein response (UPR) signaling pathways in the endoplasmic reticulum (ER), which tries to restore ER homeostasis and function. But the sustained UPR linked with inflammation, generation of ROS and apoptosis stimulates the severity of thrombosis in the body. Sirtuins, a group of seven proteins, play a vast role in bringing down inflammation, oxidative and ER stress and apoptosis. As a result, sirtuins might provide a therapeutic approach towards the treatment or prevention of hypoxia-induced thrombosis. Sirtuins modulate hypoxia-inducible factors (HIFs) and counteract ER stress-induced apoptosis by attenuating protein kinase RNA-like endoplasmic reticulum kinase (PERK)/Eukaryotic translation initiation factor 2α (eIF2α) pathway activation. It prevents ER-stress mediated inflammation by targeting X-Box Binding Protein 1 (XBP1) and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling through deacetylation. Sirtuins also obstruct nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome activation to reduce the expression of several pro-inflammatory molecules. It protects cells against oxidative stress by targeting nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), forkhead box O3 (FOXO3), superoxide dismutase (SOD), catalase (CAT), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), glucose-6-phosphate dehydrogenase (G6PD), phosphoglucomutase-2 (PGAM2), and NF-κB, to name few. This review, thus, discusses the potential role of sirtuins as a new treatment for hypoxia-induced thrombosis that involves an intersection of UPR and inflammatory pathways in its pathological manifestation.

Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9270107 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Shengjie Yang ◽

Min Wu ◽

Xiaoya Li ◽

Ran Zhao ◽

Yixi Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein ◽

Atherosclerotic Lesions ◽

Different Types ◽

Protein Response ◽

Er Homeostasis ◽

Progression Of Atherosclerosis

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats: A differential role of unfolded protein response (UPR) signaling proteins

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2012.09.017 ◽

2013 ◽

Vol 45 (2) ◽

pp. 438-447 ◽

Cited By ~ 51

Author(s):

Arun Prasath Lakshmanan ◽

Meilei Harima ◽

Kenji Suzuki ◽

Vivian Soetikno ◽

Masaki Nagata ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Diabetic Cardiomyopathy ◽

Diabetic Rats ◽

Signaling Proteins ◽

Unfolded Protein ◽

Protein Response ◽

Type 2 Diabetic

Endoplasmic Reticulum-Associated Biomarkers for Molecular Phenotyping of Rare Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22042161 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2161

Author(s):

Chuang Li ◽

Ying Maggie Chen

Keyword(s):

Endoplasmic Reticulum ◽

Kidney Disease ◽

Er Stress ◽

Protein Kinase R ◽

Post Translational Modifications ◽

Unfolded Protein ◽

Novel Biomarkers ◽

Activating Transcription Factor ◽

The endoplasmic reticulum (ER) is the central site for folding, post-translational modifications, and transport of secretory and membrane proteins. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and an unfolded protein response. Emerging evidence has shown that ER stress or the derangement of ER proteostasis contributes to the development and progression of a variety of glomerular and tubular diseases. This review gives a comprehensive summary of studies that have elucidated the role of the three ER stress signaling pathways, including inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6) signaling in the pathogenesis of kidney disease. In addition, we highlight the recent discovery of ER-associated biomarkers, including MANF, ERdj3, ERdj4, CRELD2, PDIA3, and angiogenin. The implementation of these novel biomarkers may accelerate early diagnosis and therapeutic intervention in rare kidney disease.

The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

International Journal of Molecular Sciences ◽

10.3390/ijms20071783 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1783 ◽

Cited By ~ 3

Author(s):

Takasugi ◽

Hiraoka ◽

Nakahara ◽

Akiyama ◽

Fujikawa ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Proteins ◽

Unfolded Protein ◽

Stress Sensors ◽

Protein Response ◽

Protein Disulfide ◽

The Relationship

The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.

Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8830880 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Sagir Mustapha ◽

Mustapha Mohammed ◽

Ahmad Khusairi Azemi ◽

Ismaeel Yunusa ◽

Aishatu Shehu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Molecular Mechanisms ◽

Unfolded Protein ◽

Metabolic Functions ◽

Chronic Hyperglycemia ◽

Obesity And Diabetes ◽

Activating Transcription Factor ◽

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.

Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

International Journal of Molecular Sciences ◽

10.3390/ijms22052567 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2567

Author(s):

Yann S. Gallot ◽

Kyle R. Bohnert

Keyword(s):

Skeletal Muscle ◽

Er Stress ◽

Unfolded Protein Response ◽

Smooth Endoplasmic Reticulum ◽

Skeletal Muscle Atrophy ◽

Unfolded Protein ◽

The Individual ◽

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

Are cachexia-associated tumors transmitTERS of ER stress?

Biochemical Society Transactions ◽

10.1042/bst20210496 ◽

2021 ◽

Author(s):

Ana Sayuri Yamagata ◽

Paula Paccielli Freire

Keyword(s):

Er Stress ◽

Tumor Cells ◽

Cancer Cachexia ◽

Genotoxic Stress ◽

Unfolded Protein ◽

Response To Chemotherapy ◽

Protein Response ◽

Associated Tumors

Cancer cachexia is associated with deficient response to chemotherapy. On the other hand, the tumors of cachectic patients remarkably express more chemokines and have higher immune infiltration. For immunogenicity, a strong induction of the unfolded protein response (UPR) is necessary. UPR followed by cell surface exposure of calreticulin on the dying tumor cell is essential for its engulfment by macrophages and dendritic cells. However, some tumor cells upon endoplasmic reticulum (ER) stress can release factors that induce ER stress to other cells, in the so-called transmissible ER stress (TERS). The cells that received TERS produce more interleukin 6 (IL-6) and chemokines and acquire resistance to subsequent ER stress, nutrient deprivation, and genotoxic stress. Since ER stress enhances the release of extracellular vesicles (EVs), we suggest they can mediate TERS. It was found that ER stressed cachexia-inducing tumor cells transmit factors that trigger ER stress in other cells. Therefore, considering the role of EVs in cancer cachexia, the release of exosomes can possibly play a role in the process of blunting the immunogenicity of the cachexia-associated tumors. We propose that TERS can cause an inflammatory and immunosuppressive phenotype in cachexia-inducing tumors.