scholarly journals Characteristic Features and Signalling Cascade of Novel Zoonotic Coronavirus

2021 ◽  
pp. 77-84
Author(s):  
Radha M. J. ◽  
Geetika Pant
Keyword(s):  
Transmission Rate ◽  
Innate Immune Responses ◽  
Health Crisis ◽  
Virion Assembly ◽  
Unfolded Protein ◽  
Characteristic Features ◽  
Novel Therapeutic Strategies ◽  
Protein Response ◽  
Host Signal ◽  
Signalling Cascade

The outbreak of coronavirus disease 2019 (COVID-19) due to its highly virulent nature has created a health crisis worldwide. It has attracted biologists’ attention to understand the morphology, host-pathogen interaction and signalling cascade at the core level. The whole world has come to a standstill due to the contagious nature and transmission rate of this virus. To understand the risk of COVID-19 outbreak across different parts of the globe it is crucial to provide a mechanistic framework for the interrelation of comorbidities. This review chapter focuses on the characteristic features, signalling cascade, and the interplay between pathogenesis and unfolded protein response in coronavirus. Due to the complexity of the coronavirus genome and its replication cycle, our understanding of structural, non-structural and accessory proteins in virion assembly and involvement of host machinery is significant. Thus, there is an urgent need to develop effective antiviral doses and vaccines against coronavirus. Hence, updating the detailed mechanism of cross-talk between virus and host, signal and receptor and the evasion of cellular innate immune responses is of utmost importance to develop novel therapeutic strategies.

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 Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 108
Author(s):  
Hui Li ◽  
Wen Wen ◽  
Jia Luo
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Effective Treatment ◽  
Stress Responses ◽  
Treatment Strategies ◽  
Alcoholic Pancreatitis ◽  
Excessive Alcohol Consumption ◽  
Unfolded Protein ◽  
Novel Therapeutic Strategies ◽  
Protein Response

Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.

scholarly journals The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 156
Author(s):  
Natalia Siwecka ◽  
Wioletta Rozpędek-Kamińska ◽  
Adam Wawrzynkiewicz ◽  
Dariusz Pytel ◽  
J. Alan Diehl ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Fate ◽  
Stress Conditions ◽  
Molecular Characteristics ◽  
Detailed Knowledge ◽  
Drug Candidates ◽  
Unfolded Protein ◽  
Novel Therapeutic Strategies ◽  
The Unfolded Protein Response ◽  
Protein Response

Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches of the Unfolded Protein Response (UPR) signaling pathway, which is activated upon endoplasmic reticulum (ER) stress conditions. It is known to be capable of inducing both pro-survival and pro-apoptotic cellular responses, which are strictly related to numerous human pathologies. Among others, IRE1 activity has been confirmed to be increased in cancer, neurodegeneration, inflammatory and metabolic disorders, which are associated with an accumulation of misfolded proteins within ER lumen and the resulting ER stress conditions. Emerging evidence suggests that genetic or pharmacological modulation of IRE1 may have a significant impact on cell viability, and thus may be a promising step forward towards development of novel therapeutic strategies. In this review, we extensively describe the structural analysis of IRE1 molecule, the molecular dynamics associated with IRE1 activation, and interconnection between it and the other branches of the UPR with regard to its potential use as a therapeutic target. Detailed knowledge of the molecular characteristics of the IRE1 protein and its activation may allow the design of specific kinase or RNase modulators that may act as drug candidates.

scholarly journals Bid as a novel interacting partner of IRE1 differentially regulating its RNAse activity

2019 ◽  
Author(s):  
Samirul Bashir ◽  
Debnath Pal ◽  
Mariam Banday ◽  
Ozaira Qadri ◽  
Arif Bashir ◽  
...  
Keyword(s):  
Protein Structure ◽  
Unfolded Protein Response ◽  
Kinase Domain ◽  
Structural Flexibility ◽  
Huge Number ◽  
Downstream Target ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Protein Response ◽  
Signalling Cascade

AbstractUnfolded protein response is a dynamic signalling pathway, which is involved in the maintenance of proteostasis and cellular homeostasis. IRE1, a transmembrane signalling protein represents the start point of a highly conserved UPR signalling cascade. IRE1 is endowed with kinase and endoribonuclease activities. The activation of the kinase domain of IRE1 by trans-autophosphorylation leads to the activation of its RNAse domain. RNAse domain performs atypical splicing of Xbp1 mRNA and degradation of mRNAs by an effector function known as Regulated IRE1 Dependent Decay (RIDD). The regulation of the distinctive nature of the IRE1 ribonuclease function is potentially mediated by a dynamic protein structure UPRosome that is an assembly of a huge number of proteins on IRE1. Here, we reported that Bid is a novel recruit to UPRosome, which directly interacts with the cytoplasmic domain of IRE1. Bid controls the auto-phosphorylation of IRE1 in a negative manner where Bid overexpression conditions displayed reduced phosphorylation levels of IRE1 and Bid knockdown cells showed slightly enhanced IRE1 phosphorylation. This effect was reciprocated with JNK, a downstream target of IRE1. Our Insilico analysis revealed that Bid binding to IRE1 dimer averts its structural flexibility and thereby preventing its trans-autophosphorylation activity. We found that the effect of Bid is specific to the IRE1 branch of UPR signalling and competitive in nature. The highlighting observation of the study was that Bid stimulated a differential activity of the IRE1 RNAse domain towards Xbp1 splicing and RIDD. These results together establish that Bid is a part of the UPRosome and modulates IRE1 in a way to differentially regulate its RNAse outputs.

scholarly journals Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

2021 ◽  
Author(s):  
Hui Li ◽  
Wen Wen ◽  
Jia Luo
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Effective Treatment ◽  
Stress Responses ◽  
Treatment Strategies ◽  
Alcoholic Pancreatitis ◽  
Excessive Alcohol Consumption ◽  
Unfolded Protein ◽  
Novel Therapeutic Strategies ◽  
Protein Response

Pancreatitis and alcoholic pancreatitis are serious health concerns, and there is an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR for developing novel therapeutic strategies for the disease.

Unfolded protein response pathway, IRE1[alpha]-XBP1 is altered during adipogenesis in obese human adipocytes

2013 ◽  
pp. 1-1
Author(s):  
Philip Voyias ◽  
Ciara McCarthy ◽  
Adaikala Antonysunil ◽  
Warunee Kumsaiyai ◽  
Alison Harte ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Human Adipocytes ◽  
Unfolded Protein ◽  
Obese Human ◽  
Protein Response

Oestrogen-driven changes in the bovine uterus are associated with activation of the unfolded protein response

2014 ◽  
Author(s):  
Mohammed A Alfattah ◽  
Paul Anthony McGettigan ◽  
John Arthur Browne ◽  
Khalid M Alkhodair ◽  
Katarzyna Pluta ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Native Ubiquitin Structural Changes Resulting from Complexation with β-methylamino-L-alanine (BMAA)

2020 ◽  
Author(s):  
Katie Mae Wilson ◽  
Aurora Burkus-Matesevac ◽  
Samuel Maddox ◽  
Christopher Chouinard
Keyword(s):  
Structural Changes ◽  
Noncovalent Complex ◽  
Unfolded Protein ◽  
Protein Size ◽  
High Concentrations ◽  
The Unfolded Protein Response ◽  
Critical Binding ◽  
Protein Response ◽  
The Brain ◽  
Lateral Sclerosis

β-methylamino-L-alanine (BMAA) has been linked to the development of neurodegenerative (ND) symptoms following chronic environmental exposure through water and dietary sources. The brains of those affected by this condition, often referred to as amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), have exhibited the presence of plaques and neurofibrillary tangles (NFTs) from protein aggregation. Although numerous studies have sought to better understand the correlation between BMAA exposure and onset of ND symptoms, no definitive link has been identified. One prevailing hypothesis is that BMAA acts a small molecule ligand, complexing with critical proteins in the brain and reducing their function. The objective of this research was to investigate the effects of BMAA exposure on the native structure of ubiquitin. We hypothesized that formation of a Ubiquitin+BMAA noncovalent complex would alter the protein’s structure and folding and ultimately affect the ubiquitinproteasome system (UPS) and the unfolded protein response (UPR). Ion mobility-mass spectrometry revealed that at sufficiently high concentrations BMAA did in fact form a noncovalent complex with ubiquitin, however similar complexes were identified for a range of additional amino acids. Collision induced unfolding (CIU) was used to interrogate the unfolding dynamics of native ubiquitin and these Ubq-amino acid complexes and it was determined that complexation with BMAA led to a significant alteration in native protein size and conformation, and this complex required considerably more energy to unfold. This indicates that the complex remains more stable under native conditions and this may indicate that BMAA has attached to a critical binding location.

Native Ubiquitin Structural Changes Resulting from Complexation with β-methylamino-L-alanine (BMAA)

2020 ◽  
Author(s):  
Katie Mae Wilson ◽  
Aurora Burkus-Matesevac ◽  
Samuel Maddox ◽  
Christopher Chouinard
Keyword(s):  
Structural Changes ◽  
Noncovalent Complex ◽  
Unfolded Protein ◽  
Protein Size ◽  
High Concentrations ◽  
The Unfolded Protein Response ◽  
Critical Binding ◽  
Protein Response ◽  
The Brain ◽  
Lateral Sclerosis

β-methylamino-L-alanine (BMAA) has been linked to the development of neurodegenerative (ND) symptoms following chronic environmental exposure through water and dietary sources. The brains of those affected by this condition, often referred to as amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), have exhibited the presence of plaques and neurofibrillary tangles (NFTs) from protein aggregation. Although numerous studies have sought to better understand the correlation between BMAA exposure and onset of ND symptoms, no definitive link has been identified. One prevailing hypothesis is that BMAA acts a small molecule ligand, complexing with critical proteins in the brain and reducing their function. The objective of this research was to investigate the effects of BMAA exposure on the native structure of ubiquitin. We hypothesized that formation of a Ubiquitin+BMAA noncovalent complex would alter the protein’s structure and folding and ultimately affect the ubiquitinproteasome system (UPS) and the unfolded protein response (UPR). Ion mobility-mass spectrometry revealed that at sufficiently high concentrations BMAA did in fact form a noncovalent complex with ubiquitin, however similar complexes were identified for a range of additional amino acids. Collision induced unfolding (CIU) was used to interrogate the unfolding dynamics of native ubiquitin and these Ubq-amino acid complexes and it was determined that complexation with BMAA led to a significant alteration in native protein size and conformation, and this complex required considerably more energy to unfold. This indicates that the complex remains more stable under native conditions and this may indicate that BMAA has attached to a critical binding location.

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