Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces

A number of pathophysiological insults lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) and cause ER stress. In response to accumulation of unfolded/misfolded proteins, cells adapt themselves to the stress condition via the unfolded protein response (UPR). For the cells, UPR is a double-edged sword. It triggers both prosurvival and proapoptotic signals. ER stress and UPR may, therefore, be involved in a diverse range of pathological situations. However, currently, information is limited regarding roles of ER stress and UPR in the renal pathophysiology. This review describes current knowledge on the relationship between ER stress and diseases and summarizes evidence for the link between ER stress/UPR and renal diseases.

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Methods for Monitoring Endoplasmic Reticulum Stress and the Unfolded Protein Response

International Journal of Cell Biology ◽

10.1155/2010/830307 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 132

Author(s):

Afshin Samali ◽

Una FitzGerald ◽

Shane Deegan ◽

Sanjeev Gupta

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Model Systems ◽

Unfolded Proteins ◽

Unfolded Protein ◽

Cellular Repair ◽

Standard Set ◽

The Unfolded Protein Response ◽

Protein Response

The endoplasmic reticulum (ER) is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the endoplasmic reticulum cause ER stress and activate a set of signaling pathways termed the Unfolded Protein Response (UPR). The UPR can promote cellular repair and sustained survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field. There are also many researchers not working directly on ER stress, but who wish to determine whether this response is activated in the system they are studying: thus, it is important to list a standard set of criteria for monitoring UPR in different model systems. Here, we discuss approaches that can be used by researchers to plan and interpret experiments aimed at evaluating whether the UPR and related processes are activated. We would like to emphasize that no individual assay is guaranteed to be the most appropriate one in every situation and strongly recommend the use of multiple assays to verify UPR activation.

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ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

Biomolecules ◽

10.3390/biom11020199 ◽

2021 ◽

Vol 11 (2) ◽

pp. 199

Author(s):

Kelly Féral ◽

Manon Jaud ◽

Céline Philippe ◽

Doriana Di Bella ◽

Stéphane Pyronnet ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Current Knowledge ◽

Leukemic Cells ◽

Unfolded Protein ◽

Cell Death Program ◽

Activating Transcription Factor ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)—allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases.

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Activation of Mammalian Unfolded Protein Response Is Compatible with the Quality Control System Operating in the Endoplasmic Reticulum

Molecular Biology of the Cell ◽

10.1091/mbc.e03-09-0693 ◽

2004 ◽

Vol 15 (6) ◽

pp. 2537-2548 ◽

Cited By ~ 64

Author(s):

Satomi Nadanaka ◽

Hiderou Yoshida ◽

Fumi Kano ◽

Masayuki Murata ◽

Kazutoshi Mori

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Control System ◽

Golgi Apparatus ◽

Er Stress ◽

Unfolded Protein Response ◽

Secretory Pathway ◽

Unfolded Proteins ◽

Unfolded Protein ◽

Protein Response

Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.

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The PGRS Domain of Mycobacterium tuberculosis PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4

mBio ◽

10.1128/mbio.01017-18 ◽

2018 ◽

Vol 9 (3) ◽

Cited By ~ 19

Author(s):

Sonam Grover ◽

Tarina Sharma ◽

Yadvir Singh ◽

Sakshi Kohli ◽

Manjunath P. ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Mycobacterium Tuberculosis ◽

Er Stress ◽

Unfolded Protein Response ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Content Type ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

ABSTRACT The genome of Mycobacterium tuberculosis , the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca 2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism. IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms20040857 ◽

2019 ◽

Vol 20 (4) ◽

pp. 857 ◽

Cited By ~ 20

Author(s):

Lorenza Sisinni ◽

Michele Pietrafesa ◽

Silvia Lepore ◽

Francesca Maddalena ◽

Valentina Condelli ◽

...

Keyword(s):

Breast Cancer ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Inflammatory Diseases ◽

Unfolded Protein ◽

Chronic Activation ◽

The Unfolded Protein Response ◽

Protein Response ◽

The Relationship

The unfolded protein response (UPR) is a stress response activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) and its uncontrolled activation is mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, and inflammatory diseases, and cancer. Indeed, ER stress and the downstream UPR activation lead to changes in the levels and activities of key regulators of cell survival and autophagy and this is physiologically finalized to restore metabolic homeostasis with the integration of pro-death or/and pro-survival signals. By contrast, the chronic activation of UPR in cancer cells is widely considered a mechanism of tumor progression. In this review, we focus on the relationship between ER stress, apoptosis, and autophagy in human breast cancer and the interplay between the activation of UPR and resistance to anticancer therapies with the aim to disclose novel therapeutic scenarios. The hypothesis that autophagy and UPR may provide novel molecular targets in human malignancies is discussed.

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Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0306 ◽

2016 ◽

Vol 57 (1) ◽

pp. R1-R17 ◽

Cited By ~ 31

Author(s):

Kira Meyerovich ◽

Fernanda Ortis ◽

Florent Allagnat ◽

Alessandra K Cardozo

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Diabetic Patients ◽

Β Cells ◽

Β Cell ◽

Unfolded Protein ◽

Islet Inflammation ◽

The Unfolded Protein Response ◽

Protein Response

Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

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Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude

eLife ◽

10.7554/elife.27518 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 26

Author(s):

Anush Bakunts ◽

Andrea Orsi ◽

Milena Vitale ◽

Angela Cattaneo ◽

Federica Lari ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Heavy Chain ◽

Immunoglobulin M ◽

Unfolded Protein ◽

Er Chaperone ◽

Ideal System ◽

The Unfolded Protein Response ◽

Protein Response

Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves ER homeostatic readjustment is poorly investigated, as in most studies the ER stress that is elicited cannot be overcome. Here we show that a proteostatic insult, provoked by persistent expression of the secretory heavy chain of immunoglobulin M (µs), is well-tolerated in HeLa cells. Upon µs expression, its levels temporarily eclipse those of the ER chaperone BiP, leading to acute, full-geared UPR activation. Once BiP is in excess again, the UPR transitions to chronic, submaximal activation, indicating that the UPR senses ER stress in a ratiometric fashion. In this process, the ER expands about three-fold and becomes dominated by BiP. As the UPR is essential for successful ER homeostatic readjustment in the HeLa-µs model, it provides an ideal system for dissecting the intricacies of how the UPR evaluates and alleviates ER stress.

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