The Unfolded Protein Response in the Immune Cell Development: Putting the Caretaker in the Driving Seat

Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function

International Journal of Molecular Sciences ◽

10.3390/ijms20071792 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1792 ◽

Cited By ~ 4

Author(s):

Kyeorda Kemp ◽

Cody Poe

Keyword(s):

Endoplasmic Reticulum ◽

T Cell ◽

Unfolded Protein Response ◽

T Cell Development ◽

Cell Development ◽

Secretory Cells ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

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The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13174443 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4443

Author(s):

Ankit Patel ◽

Masanori Oshi ◽

Li Yan ◽

Ryusei Matsuyama ◽

Itaru Endo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Unfolded Protein Response ◽

Cancer Progression ◽

Cancer Biology ◽

Immune Cell ◽

Histological Grade ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.

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Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

10.20944/preprints202012.0578.v2 ◽

2021 ◽

Author(s):

Chao Li

Keyword(s):

Er Stress ◽

Unfolded Protein Response ◽

Immune Cell ◽

Macrophage Polarization ◽

Intestinal Epithelial ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of inflammatory bowel disease (IBD) including Crohn’s disease. Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of UPR in the pathogenesis in IBD from an immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways such as senescence and autophagy are introduced. Recent advances in the understanding of the epigenetic regulation of UPR signaling are also updated here. The future directions of development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.

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Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

Gastrointestinal Disorders ◽

10.3390/gidisord3010004 ◽

2021 ◽

Vol 3 (1) ◽

pp. 31-43

Author(s):

Chao Li

Keyword(s):

Er Stress ◽

Unfolded Protein Response ◽

Immune Cell ◽

Macrophage Polarization ◽

Intestinal Epithelial ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs, including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD). Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of the UPR in the pathogenesis in IBD from an immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways, such as senescence and autophagy, are introduced. Recent advances in the understanding of the epigenetic regulation of the UPR signaling are also updated here. The future directions of development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.

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The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.682633 ◽

2021 ◽

Vol 13 ◽

Author(s):

Dominique Fernández ◽

Antonia Geisse ◽

Jose Ignacio Bernales ◽

Alonso Lira ◽

Fabiola Osorio

Keyword(s):

Neurodegenerative Diseases ◽

Unfolded Protein Response ◽

Immune Cells ◽

Immune Cell ◽

Immune Surveillance ◽

Potential Contribution ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response

Immune surveillance is an essential process that safeguards the homeostasis of a healthy brain. Among the increasing diversity of immune cells present in the central nervous system (CNS), microglia have emerged as a prominent leukocyte subset with key roles in the support of brain function and in the control of neuroinflammation. In fact, impaired microglial function is associated with the development of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Interestingly, these pathologies are also typified by protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER). These processes trigger activation of the unfolded protein response (UPR), which is a conserved signaling network that maintains the fidelity of the cellular proteome. Remarkably, beyond its role in protein folding, the UPR has also emerged as a key regulator of the development and function of immune cells. However, despite this evidence, the contribution of the UPR to immune cell homeostasis, immune surveillance, and neuro-inflammatory processes remains largely unexplored. In this review, we discuss the potential contribution of the UPR in brain-associated immune cells in the context of neurodegenerative diseases.

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Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

International Journal of Molecular Sciences ◽

10.3390/ijms21010169 ◽

2019 ◽

Vol 21 (1) ◽

pp. 169 ◽

Cited By ~ 2

Author(s):

Manuel U. Ramirez ◽

Salvador R. Hernandez ◽

David R. Soto-Pantoja ◽

Katherine L. Cook

Keyword(s):

Immune Response ◽

Endoplasmic Reticulum ◽

Unfolded Protein Response ◽

Cancer Progression ◽

Cell Function ◽

Immune Cell ◽

Stressful Events ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Despite advances in cancer therapy, several persistent issues remain. These include cancer recurrence, effective targeting of aggressive or therapy-resistant cancers, and selective treatments for transformed cells. This review evaluates the current findings and highlights the potential of targeting the unfolded protein response to treat cancer. The unfolded protein response, an evolutionarily conserved pathway in all eukaryotes, is initiated in response to misfolded proteins accumulating within the lumen of the endoplasmic reticulum. This pathway is initially cytoprotective, allowing cells to survive stressful events; however, prolonged activation of the unfolded protein response also activates apoptotic responses. This balance is key in successful mammalian immune response and inducing cell death in malignant cells. We discuss how the unfolded protein response affects cancer progression, survival, and immune response to cancer cells. The literature shows that targeting the unfolded protein response as a monotherapy or in combination with chemotherapy or immunotherapies increases the efficacy of these drugs; however, systemic unfolded protein response targeting may yield deleterious effects on immune cell function and should be taken into consideration. The material in this review shows the promise of both approaches, each of which merits further research.

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B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m801395200 ◽

2008 ◽

Vol 283 (26) ◽

pp. 17954-17961 ◽

Cited By ~ 56

Author(s):

Ryan Brunsing ◽

Sidne A. Omori ◽

Frank Weber ◽

Alicia Bicknell ◽

Leslie Friend ◽

...

Keyword(s):

T Cell ◽

Unfolded Protein Response ◽

T Cell Development ◽

Cell Development ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

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Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

10.20944/preprints202012.0578.v1 ◽

2020 ◽

Author(s):

Chao Li

Keyword(s):

Er Stress ◽

Unfolded Protein Response ◽

Immune Cell ◽

Macrophage Polarization ◽

Intestinal Epithelial ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of inflammatory bowel disease (IBD) including Crohn’s disease. Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of UPR in the pathogenesis in IBD from immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways such as senescence and autophagy are introduced. Recent advances in the understanding of the epigenetic regulation of UPR signaling are reported. The future directions of the development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.

Download Full-text