scholarly journals ER Stress, UPR Activation and the Inflammatory Response to Viral Infection

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 798
Author(s):  
Mara Cirone
Keyword(s):  
Inflammatory Response ◽  
Viral Infection ◽  
Viral Infections ◽  
Protective Role ◽  
Microbial Infection ◽  
Unfolded Protein ◽  
Cytokines And Chemokines ◽  
Complex Process ◽  
Protein Response ◽  
Recognition Receptor

The response to invading pathogens such as viruses is orchestrated by pattern recognition receptor (PRR) and unfolded protein response (UPR) signaling, which intersects and converges in the activation of proinflammatory pathways and the release of cytokines and chemokines that harness the immune system in the attempt to clear microbial infection. Despite this protective intent, the inflammatory response, particularly during viral infection, may be too intense or last for too long, whereby it becomes the cause of organ or systemic diseases itself. This suggests that a better understanding of the mechanisms that regulate this complex process is needed in order to achieve better control of the side effects that inflammation may cause while potentiating its protective role. The use of specific inhibitors of the UPR sensors or PRRs or the downstream pathways activated by their signaling could offer the opportunity to reach this goal and improve the outcome of inflammation-based diseases associated with viral infections.

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 Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24

2018 ◽  
Vol 315 (2) ◽  
pp. G318-G327 ◽  
Author(s):  
Geeta Rao ◽  
Hailey Houson ◽  
Gregory Nkepang ◽  
Hooman Yari ◽  
Chengwen Teng ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Hemorrhagic Shock ◽  
Unfolded Protein Response ◽  
Systemic Inflammatory Response ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Unfolded Protein ◽  
Protein Response

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock. CLEFMA or EF24 (0.4 mg/kg) were given 1 h after withdrawing 50% of blood from Sprague-Dawley rats; no other resuscitation was provided. After another 5 h of compensation, small gut was collected to process tissue for proteasome activity, immunoblotting, and mRNA levels of genes responsible for unfolded-protein response (XBP1, ATF4, glucose-regulated protein of 78/95 kDa, and growth arrest and DNA damage inducible genes 153/34), polyubiquitin B and C, and immunoproteasome subunits β type-8 and -10 and proteasome activator subunit 1. We found that hemorrhagic shock induced proteasome activity in gut tissue and reduced the amounts of ubiquitinated proteins displayed on antiubiquitin immunoblots. However, simultaneous induction of unfolded-protein response or immunoproteasome genes was not observed. CLEFMA and EF24 treatments abolished the hemorrhagic shock-induced increase in proteasome activity. Further investigations revealed that the induction of proteasome in hemorrhagic shock is associated with disassembly of 26S proteasome; CLEFMA and EF24 prevented this disassembly. Consistent with these data, CLEFMA and EF24 reduced hemorrhagic shock-induced degradation of 20S substrate ornithine decarboxylase in gut tissue. These results suggest that activated proteasome plays an important role in ischemic gut pathophysiology, and it can be a druggable target in shock-induced gut dysfunction. NEW & NOTEWORTHY Ischemic injury to the gut is a trigger for the systemic inflammatory response and multiple organ failure in trauma and hemorrhagic shock. We show for the first time that hemorrhagic shock induces the gut proteasome activity by engendering 26S proteasome disassembly. Diphenyldihaloketones 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone treatment prevented the 26S disassembly. Understanding the role of proteasome in shock-associated gut injury will assist in the development of therapeutic means to address it.

scholarly journals Synbiotic combination of prebiotic grape pomace extract and probiotic Lactobacillus sp. reduced important intestinal inflammatory markers and in-depth signalling mediators in lipopolysaccharide-treated Caco-2 cells

2018 ◽  
Vol 121 (3) ◽  
pp. 291-305 ◽  
Author(s):  
Gina Cecilia Pistol ◽  
Daniela Eliza Marin ◽  
Catalin Dragomir ◽  
Ionelia Taranu
Keyword(s):  
Inflammatory Markers ◽  
Life Quality ◽  
Protective Role ◽  
Grape Pomace ◽  
Mitogen Activated Protein Kinase ◽  
New Combination ◽  
Microbial Infection ◽  
Signalling Molecules ◽  
Aryl Hydrocarbon ◽  
Cytokines And Chemokines

AbstractInflammatory bowel diseases (IBD) are a major problem for public health, with an increased incidence and impact on life quality. The effect of pre- and probiotic combination has been less studied in IBD. Using genomic and proteomic array technologies, this study examined the efficacy of a new combination of natural alternatives: prebiotics (grape pomace extract, GP) and probiotics (lactobacilli mixture, Lb mix) on inflammation and intracellular signalling routes in a cellular model of inflammation. Caco-2 cells challenged with lipopolysaccharide (LPS) for 4 h were treated with GP extract (50 μg/ml gallic acid equivalent) and Lb combination (3 × 108 colony-forming units/ml total Lb) for 24 h. The profile expressions of forty key inflammatory markers and twenty-six signalling kinases were analysed. Other markers involved in inflammation were also investigated (NF-κB/RELA, Nrf2, aryl hydrocarbon receptor, Cyp1A1, Cyp1B1); 57·5 and 60 % of investigated genes and proteins, respectively, were down-regulated by the synbiotic combination. Relevant cytokines and chemokines involved in response to microbial infection and inflammation were reduced under the level induced by LPS treatment and toward the unchallenged control. As expected, the reduction effect seems to imply mitogen-activated protein kinase and NF-κB pathway. Most of the signalling molecules activated by LPS were decreased by GP extract and Lb mix. Our study indicates that the synbiotic combination of GP extract and Lactobacillus sp. mixture exerted anti-inflammatory properties, which are able to decrease the majority of inflammatory genes, their proteins and associated signalling markers. Due to protective role of GP compounds on lactobacilli probiotic, this synbiotic combination might serve as a promising adjunctive therapy in intestinal inflammations.

scholarly journals Human Cytomegalovirus Infection Activates and Regulates the Unfolded Protein Response

2005 ◽  
Vol 79 (11) ◽  
pp. 6890-6899 ◽  
Author(s):  
Jennifer A. Isler ◽  
Alison H. Skalet ◽  
James C. Alwine
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Viral Infection ◽  
Unfolded Protein Response ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Viral infection causes stress to the endoplasmic reticulum. The response to endoplasmic reticulum stress, known as the unfolded protein response (UPR), is designed to eliminate misfolded proteins and allow the cell to recover by attenuating translation and upregulating the expression of chaperones, degradation factors, and factors that regulate the cell's metabolic and redox environment. Some consequences of the UPR (e.g., expression of chaperones and regulation of the metabolism and redox environment) may be advantageous to the viral infection; however, translational attenuation would not. Thus, viruses may induce mechanisms which modulate the UPR, maintaining beneficial aspects and suppressing deleterious aspects. We demonstrate that human cytomegalovirus (HCMV) infection induces the UPR but specifically regulates the three branches of UPR signaling, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE-1), to favor viral replication. HCMV infection activated the eIF2α kinase PERK; however, the amount of phosphorylated eIF2α was limited and translation attenuation did not occur. Interestingly, translation of select mRNAs, which is dependent on eIF2α phosphorylation, did occur, including the transcription factor ATF4, which activates genes which may benefit the infection. The endoplasmic reticulum stress-induced activation of the transcription factor ATF6 was suppressed in HCMV-infected cells; however, specific chaperone genes, normally activated by ATF6, were activated by a virus-induced, ATF6-independent mechanism. Lastly, HCMV infection activated the IRE-1 pathway, as indicated by splicing of Xbp-1 mRNA. However, transcriptional activation of the XBP-1 target gene EDEM (ER degradation-enhancing α-mannosidase-like protein, a protein degradation factor) was inhibited. These results suggest that, although HCMV infection induces the unfolded protein response, it modifies the outcome to benefit viral replication.

scholarly journals Immunoregulation of the decidualization program: focus on the endoplasmic reticulum stress

Reproduction ◽  
2020 ◽  
Vol 159 (4) ◽  
pp. R203-R211 ◽  
Author(s):  
Elizabeth Soczewski ◽  
Esteban Grasso ◽  
Lucila Gallino ◽  
Vanesa Hauk ◽  
Laura Fernández ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Inflammatory Response ◽  
Er Stress ◽  
Stromal Cells ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Embryo Implantation ◽  
Endometrial Stromal Cells ◽  
Unfolded Protein ◽  
Protein Response

Decidualization denotes the reprogramming of endometrial stromal cells that includes the secretion of different mediators like cytokines, chemokines, and the selective recruitment of immune cells. This physiological process involves changes in the secretome of the endometrial stromal cells leading to the production of immunomodulatory factors. The increased amount of protein secretion is associated with a physiological endoplasmic reticulum (ER) stress and the resulting unfolded protein response (UPR), allowing the expansion of ER and the machinery to assist the protein folding. Notably, the signaling pathways involved in the ER stress and the UPR are interconnected with the onset of a sterile inflammatory response, as well as with angiogenesis. Both of these processes have a key role in decidualization and placentation, therefore, alterations in them could lead to pregnancy complications. In this review, we will discuss how the induction of ER stress and the UPR processes that accompanies the decidualization are associated with embryo implantation and whether they might condition pregnancy outcome. The ER stress activates/triggers sensing proteins which, among others, induces kinase/RNAse-TXNIP expression, activating the NLRP3 inflammasome. This multiprotein system allows caspase-1 activation, which catalyzes the cleavage of the inactive IL-1β proform toward the mature secretory form, with pro-implantatory effects. However, the sterile inflammatory response should be later controlled in favor of a tolerogenic microenvironment to sustain pregnancy. In accordance, alterations of the ER stress and UPR processes can be reflected in recurrent implantation failures (RIF), recurrent pregnancy loss (RPL), or complications associated with deficient placentation, such as preeclampsia (PE).

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 Immune regulation of the unfolded protein response at the mucosal barrier in viral infection

2018 ◽  
Vol 7 (4) ◽  
pp. e1014 ◽  
Author(s):  
Ran Wang ◽  
Md. Moniruzzaman ◽  
Eric Shuffle ◽  
Rohan Lourie ◽  
Sumaira Z Hasnain
Keyword(s):  
Viral Infection ◽  
Unfolded Protein Response ◽  
Immune Regulation ◽  
Mucosal Barrier ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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