Targeting unfolded protein response: a new horizon for disease control

2021 ◽  
Vol 23 ◽  
Author(s):  
Madhu Khanna ◽  
Nishtha Agrawal ◽  
Ramesh Chandra ◽  
Gagan Dhawan
Keyword(s):  
Unfolded Protein Response ◽  
Disease Progression ◽  
Viral Infections ◽  
Cancer Type ◽  
Unfolded Protein ◽  
Diseased State ◽  
Protein Response ◽  
And Control ◽  
Er Homeostasis ◽  
Signalling Cascade

Abstract Unfolded protein response (UPR) is an evolutionarily conserved pathway triggered during perturbation of endoplasmic reticulum (ER) homeostasis in response to the accumulation of unfolded/misfolded proteins under various stress conditions like viral infection, diseased states etc. It is an adaptive signalling cascade with the main purpose of relieving the stress from the ER, which may otherwise lead to the initiation of cell death via apoptosis. ER stress if prolonged, contribute to the aetiology of various diseases like cancer, type II diabetes, neurodegenerative diseases, viral infections etc. Understanding the role of UPR in disease progression will help design pharmacological drugs targeting the sensors of signalling cascade acting as potential therapeutic agents against various diseases. The current review aims at highlighting the relevance of different pathways of UPR in disease progression and control, including the available pharmaceutical interventions responsible for ameliorating diseased state via modulating UPR pathways.

scholarly journals Two Distinctly Localized P-Type ATPases Collaborate to Maintain Organelle Homeostasis Required for Glycoprotein Processing and Quality Control

2002 ◽  
Vol 13 (11) ◽  
pp. 3955-3966 ◽  
Author(s):  
Shilpa Vashist ◽  
Christian G. Frank ◽  
Claude A. Jakob ◽  
Davis T.W. Ng
Keyword(s):  
Quality Control ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Ion Homeostasis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Coa Reductase ◽  
Protein Response ◽  
P Type ◽  
Er Homeostasis

Membrane transporter proteins are essential for the maintenance of cellular ion homeostasis. In the secretory pathway, the P-type ATPase family of transporters is found in every compartment and the plasma membrane. Here, we report the identification of COD1/SPF1(control of HMG-CoA reductase degradation/SPF1) through genetic strategies intended to uncover genes involved in protein maturation and endoplasmic reticulum (ER)-associated degradation (ERAD), a quality control pathway that rids misfolded proteins. Cod1p is a putative ER P-type ATPase whose expression is regulated by the unfolded protein response, a stress-inducible pathway used to monitor and maintain ER homeostasis. COD1 mutants activate the unfolded protein response and are defective in a variety of functions apart from ERAD, which further support a homeostatic role.COD1 mutants display phenotypes similar to strains lacking Pmr1p, a Ca2+/Mn2+pump that resides in the medial-Golgi. Because of its localization, the previously reported role of PMR1 in ERAD was somewhat enigmatic. A clue to their respective roles came from observations that the two genes are not generally required for ERAD. We show that the specificity is rooted in a requirement for both genes in protein-linked oligosaccharide trimming, a requisite ER modification in the degradation of some misfolded glycoproteins. Furthermore, Cod1p, like Pmr1p, is also needed for the outer chain modification of carbohydrates in the Golgi apparatus despite its ER localization. In strains deleted of both genes, these activities are nearly abolished. The presence of either protein alone, however, can support partial function for both compartments. Taken together, our results reveal an interdependent relationship between two P-type ATPases to maintain homeostasis of the organelles where they reside.

scholarly journals Phosphorylation of Pal2 by the protein kinases Kin1 and Kin2 modulates HAC1 mRNA splicing in the unfolded protein response in yeast

2021 ◽  
Vol 14 (684) ◽  
pp. eaaz4401
Author(s):  
Chandrima Ghosh ◽  
Jagadeesh Kumar Uppala ◽  
Leena Sathe ◽  
Charlotte I. Hammond ◽  
Ashish Anshu ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Protein Kinases ◽  
Cellular Stress ◽  
Mrna Processing ◽  
Mrna Splicing ◽  
Cellular Stress Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

During cellular stress in the budding yeast Saccharomyces cerevisiae, an endoplasmic reticulum (ER)–resident dual kinase and RNase Ire1 splices an intron from HAC1 mRNA in the cytosol, thereby releasing its translational block. Hac1 protein then activates an adaptive cellular stress response called the unfolded protein response (UPR) that maintains ER homeostasis. The polarity-inducing protein kinases Kin1 and Kin2 contribute to HAC1 mRNA processing. Here, we showed that an RNA-protein complex that included the endocytic proteins Pal1 and Pal2 mediated HAC1 mRNA splicing downstream of Kin1 and Kin2. We found that Pal1 and Pal2 bound to the 3′ untranslated region (3′UTR) of HAC1 mRNA, and a yeast strain lacking both Pal1 and Pal2 was deficient in HAC1 mRNA processing. We also showed that Kin1 and Kin2 directly phosphorylated Pal2, and that a nonphosphorylatable Pal2 mutant could not rescue the UPR defect in a pal1Δ pal2Δ strain. Thus, our work uncovers a Kin1/2-Pal2 signaling pathway that coordinates HAC1 mRNA processing and ER homeostasis.

Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency

2008 ◽  
Vol 45 (10) ◽  
pp. 2990-2997 ◽  
Author(s):  
Juliana S. Kuribayashi ◽  
Cíntia R. Bombardieri ◽  
Gisele V. Baracho ◽  
Júlio Aliberti ◽  
Fabiana S. Machado ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Common Variable Immunodeficiency ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Common Variable

scholarly journals Modulation of SARS-CoV-2 Spike-induced Unfolded Protein Response (UPR) in HEK293T cells by selected small chemical molecules

2021 ◽  
Author(s):  
Bijina Balakrishnan ◽  
Kent Lai
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Viral Infections ◽  
Host Cells ◽  
Transfected Cells ◽  
Unfolded Protein ◽  
Infected Cells ◽  
Protein Response ◽  
Small Chemical ◽  
Stress Activation

Coronaviruses (CoV) exploits the endoplasmic reticulum (ER) of the host cells for replication and in doing so, increases ER stress. evokes Unfolded Protein Response (UPR) and possibly autophagy, which could all attribute to the pathophysiology of the viral infections. To date, little is known about the roles of ER stress, UPR, and autophagy in SARS-CoV-2 infection. Here we over-expressed the viral Spike (S) protein in cultured HEK293T cells, as it has been shown that such protein is largely responsible for UPR activation in other CoV-infected cells. We noticed, in the transfected cells, heightened ER stress, activation of the PERK-eIF2α arm of the UPR, induction of autophagy and cell death. When we treated the transfected cells with Tauroursodeoxycholic acid (TUDCA), 4-phenyl butyric acid (PBA), Salubrinal, Trazadone hydrochloride, and Dibenzoylmethane (DBM), we saw reduced the BiP/GRP78 levels, but only PBA and TUDCA could significantly diminish the levels of peIF2α and autophagy expression.

scholarly journals 3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Qiao Liu ◽  
Anthony K. N. Chan ◽  
Wen-Han Chang ◽  
Lu Yang ◽  
Sheela Pangeni Pokharel ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response ◽  
Er Homeostasis

scholarly journals The impact of the unfolded protein response on human disease

2012 ◽  
Vol 197 (7) ◽  
pp. 857-867 ◽  
Author(s):  
Shiyu Wang ◽  
Randal J. Kaufman
Keyword(s):  
Unfolded Protein Response ◽  
Human Disease ◽  
Intracellular Signaling ◽  
Central Function ◽  
Intracellular Signaling Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

scholarly journals Crosstalk between the Unfolded Protein Response and NF-κB-Mediated Inflammation in the Progression of Chronic Kidney Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Zahraa Mohammed-Ali ◽  
Gaile L. Cruz ◽  
Jeffrey G. Dickhout
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Unfolded Protein Response ◽  
Disease Progression ◽  
Chronic Kidney Disease Progression ◽  
Chronic Inflammatory Response ◽  
Unfolded Protein ◽  
Kidney Disease Progression ◽  
The Unfolded Protein Response ◽  
Protein Response

The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF-κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-κB signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF-κB pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation.

scholarly journals Pseudorabies Virus Infection Induces Endoplasmic Reticulum Stress Through PERK and IRE1 Pathways of Unfolded Protein Response

2021 ◽  
Author(s):  
Li Chen ◽  
Minshu Ni ◽  
Waqas Ahmed ◽  
Yue Xu ◽  
Xi Bao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Pseudorabies Virus ◽  
Viral Infections ◽  
Host Cells ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Enhanced Expression ◽  
Protein Response

Abstract Pseudorabies virus (PRV) is a pathogen of swine resulting in devastating disease. Some viral infections can cause endoplasmic reticulum (ER) stress and unfolded protein response (UPR) to restore ER homeostasis. However, the mechanism of how PRV induces ER stress and UPR activation remains unclear. Here, levels of proteins or transcriptional factors of three UPR pathways were examined in suspension-cultured BHK-21 cells to investigate PRV-induced ER stress. Results showed that PRV triggered ER stress and UPR of the host cells with the upregulated expression of glucose-related protein 78 kD and 94 kD (GRP78 and GRP94). The protein kinase RNA-like ER kinase (PERK) pathway was activated to upregulate ATF4, CHOP, and GADD34 expression. Additionally, the inositol requiring kinase 1 (IRE1) pathway was triggered by splicing of X box-binding protein 1 (XBP1) mRNA and the enhanced expression of p58IPK and EDEM1. Furthermore, our data demonstrated that PRV took advantage of ER stress to accelerate its replication with the activation of the PERK and IRE1 pathways in suspension-cultured BHK-21 cells, and the glycoprotein B played a crucial role in ER stress.

scholarly journals SARS-CoV-2 ORF3a Induces Incomplete Autophagy via the Unfolded Protein Response

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2467
Author(s):  
Wenqing Su ◽  
Xuejie Yu ◽  
Chuanmin Zhou
Keyword(s):  
Unfolded Protein Response ◽  
Viral Infections ◽  
Dependent Manner ◽  
Therapeutic Modalities ◽  
Unfolded Protein ◽  
The Past ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

In the past year and a half, SARS-CoV-2 has caused 240 million confirmed cases and 5 million deaths worldwide. Autophagy is a conserved process that either promotes or inhibits viral infections. Although coronaviruses are known to utilize the transport of autophagy-dependent vesicles for the viral life cycle, the underlying autophagy-inducing mechanisms remain largely unexplored. Using several autophagy-deficient cell lines and autophagy inhibitors, we demonstrated that SARS-CoV-2 ORF3a was able to induce incomplete autophagy in a FIP200/Beclin-1-dependent manner. Moreover, ORF3a was involved in the induction of the UPR (unfolded protein response), while the IRE1 and ATF6 pathways, but not the PERK pathway, were responsible for mediating the ORF3a-induced autophagy. These results identify the role of the UPR pathway in the ORF3a-induced classical autophagy process, which may provide us with a better understanding of SARS-CoV-2 and suggest new therapeutic modalities in the treatment of COVID-19.

scholarly journals Recent advances in signal integration mechanisms in the unfolded protein response

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1840 ◽  
Author(s):  
G. Elif Karagöz ◽  
Tomás Aragón ◽  
Diego Acosta-Alvear
Keyword(s):  
Unfolded Protein Response ◽  
New Developments ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
Integration Mechanisms ◽  
Physiological Demands ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Made In

Since its discovery more than 25 years ago, great progress has been made in our understanding of the unfolded protein response (UPR), a homeostatic mechanism that adjusts endoplasmic reticulum (ER) function to satisfy the physiological demands of the cell. However, if ER homeostasis is unattainable, the UPR switches to drive cell death to remove defective cells in an effort to protect the health of the organism. This functional dichotomy places the UPR at the crossroads of the adaptation versus apoptosis decision. Here, we focus on new developments in UPR signaling mechanisms, in the interconnectivity among the signaling pathways that make up the UPR in higher eukaryotes, and in the coordination between the UPR and other fundamental cellular processes.

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