scholarly journals Role of Glutathionylation in Infection and Inflammation

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1952 ◽  
Author(s):  
Paola Checconi ◽  
Dolores Limongi ◽  
Sara Baldelli ◽  
Maria Rosa Ciriolo ◽  
Lucia Nencioni ◽  
...  
Keyword(s):  
Protein Function ◽  
Host Response ◽  
Redox State ◽  
Cellular Proteins ◽  
Host Responses ◽  
Post Translational Modification ◽  
Microbial Infections ◽  
Infection And Inflammation ◽  
Mixed Disulfides

Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.

scholarly journals Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4402
Author(s):  
Antti Kukkula ◽  
Veera K. Ojala ◽  
Lourdes M. Mendez ◽  
Lea Sistonen ◽  
Klaus Elenius ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Recent Developments ◽  
Sumo Pathway ◽  
Multiple Levels

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

Emerging Role of the Enteric Nervous System in Mediating Host Responses to Microbial Infections

2000 ◽  
Vol 30 (3) ◽  
pp. 229
Author(s):  
Robert D. Baker ◽  
Hans Büller ◽  
Philip Rosenthal ◽  
Philip M. Sherman ◽  
Philip M. Sherman
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Host Responses ◽  
Microbial Infections

IL-1β mediates leptin induction during inflammation

1998 ◽  
Vol 274 (1) ◽  
pp. R204-R208 ◽  
Author(s):  
Raffaella Faggioni ◽  
Giamila Fantuzzi ◽  
John Fuller ◽  
Charles A. Dinarello ◽  
Kenneth R. Feingold ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Food Intake ◽  
Host Response ◽  
Tumor Necrosis ◽  
Local Inflammation ◽  
Protein Levels ◽  
Infection And Inflammation ◽  
Leptin Expression ◽  
Necrosis Factor

Interleukins (IL) are key mediators of the host response to infection and inflammation. Leptin is secreted by adipose tissue and plays an important role in the control of food intake. Administration of lipopolysaccharide (LPS), tumor necrosis factor (TNF), or IL-1 acutely increases leptin mRNA and protein levels. To investigate the role of IL-1β and IL-6 in leptin expression during inflammation, we used IL-1β-deficient (−/−) and IL-6 −/− mice. Mice were injected intraperitoneally with LPS or subcutaneously with turpentine, as models of systemic or local inflammation, respectively. In IL-1β +/+ mice, both LPS and turpentine increased leptin mRNA and circulating leptin. In contrast, neither LPS nor turpentine increased leptin levels in IL-1β −/− mice. In IL-6 +/+ or IL-6 −/− mice, turpentine increased leptin protein to comparable levels. We conclude that IL-1β is essential for leptin induction by both LPS and turpentine in mice, but IL-6 is not.

scholarly journals Understanding the Role of Protein Glycation in the Amyloid Aggregation Process

2021 ◽  
Vol 22 (12) ◽  
pp. 6609
Author(s):  
Ivana Sirangelo ◽  
Clara Iannuzzi
Keyword(s):  
Protein Structure ◽  
Protein Function ◽  
The Body ◽  
Protein Glycation ◽  
Amyloid Formation ◽  
Aggregation Process ◽  
Amyloid Aggregation ◽  
Post Translational Modification

Protein function and flexibility is directly related to the native distribution of its structural elements and any alteration in protein architecture leads to several abnormalities and accumulation of misfolded proteins. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidosis characterized by the accumulation of amyloid aggregates both in the extracellular space of tissues and as intracellular deposits. Post-translational modifications are known to have an active role in the in vivo amyloid aggregation as able to affect protein structure and dynamics. Among them, a key role seems to be played by non-enzymatic glycation, the most unwanted irreversible modification of the protein structure, which strongly affects long-living proteins throughout the body. This study provided an overview of the molecular effects induced by glycation on the amyloid aggregation process of several protein models associated with misfolding diseases. In particular, we analyzed the role of glycation on protein folding, kinetics of amyloid formation, and amyloid cytotoxicity in order to shed light on the role of this post-translational modification in the in vivo amyloid aggregation process.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

scholarly journals Redox Regulation by Protein S-Glutathionylation: From Molecular Mechanisms to Implications in Health and Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8113 ◽  
Author(s):  
Aysenur Musaogullari ◽  
Yuh-Cherng Chai
Keyword(s):  
Protein Function ◽  
Liver Diseases ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Protein S ◽  
Protective Mechanism ◽  
Post Translational Modification ◽  
Physiological Processes ◽  
Health And Disease ◽  
Mixed Disulfides

S-glutathionylation, the post-translational modification forming mixed disulfides between protein reactive thiols and glutathione, regulates redox-based signaling events in the cell and serves as a protective mechanism against oxidative damage. S-glutathionylation alters protein function, interactions, and localization across physiological processes, and its aberrant function is implicated in various human diseases. In this review, we discuss the current understanding of the molecular mechanisms of S-glutathionylation and describe the changing levels of expression of S-glutathionylation in the context of aging, cancer, cardiovascular, and liver diseases.

scholarly journals The Central Role of the Inflammatory Response in Understanding the Heterogeneity of Sepsis-3

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Renyu Ding ◽  
Yulan Meng ◽  
Xiaochun Ma
Keyword(s):  
Inflammatory Response ◽  
Organ Failure ◽  
Host Response ◽  
Comprehensive Evaluation ◽  
Systemic Inflammatory Response ◽  
Host Responses ◽  
Persistent Inflammation ◽  
Failure Assessment ◽  
Definition Of

In sepsis-3, in contrast with sepsis-1, the definition “systemic inflammatory response” has been replaced with “dysregulated host response”, and “systemic inflammatory response syndrome” (SIRS) has been replaced with “sequential organ failure assessment” (SOFA). Although the definition of sepsis has changed, the debate regarding its nature is ongoing. What are the fundamental processes controlling sepsis-induced inflammation, immunosuppression, or organ failure? In this review, we discuss the heterogeneity of sepsis-3 and address the central role of inflammation in the pathogenesis of sepsis. An unbalanced pro- and anti-inflammatory response, inflammatory resolution disorder, and persistent inflammation play important roles in the acute and/or chronic phases of sepsis. Moreover, powerful links exist between inflammation and other host responses (such as the neuroendocrine response, coagulation, and immunosuppression). We suggest that a comprehensive evaluation of the role of the inflammatory response will improve our understanding of the heterogeneity of sepsis.

Role of electrophilic nitrated fatty acids during development and response to abiotic stress processes in plants

2020 ◽  
Author(s):  
Juan C Begara-Morales ◽  
Capilla Mata-Pérez ◽  
Maria N Padilla ◽  
Mounira Chaki ◽  
Raquel Valderrama ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Abiotic Stress ◽  
Stress Responses ◽  
Protein Function ◽  
Unsaturated Fatty Acids ◽  
Antioxidant Systems ◽  
Post Translational Modification ◽  
No Donor ◽  
Initial Development

Abstract Nitro-fatty acids are generated from the interaction of unsaturated fatty acids and nitric oxide (NO)-derived molecules. The endogenous occurrence and modulation throughout plant development of nitro-linolenic acid (NO2-Ln) and nitro-oleic acid (NO2-OA) suggest a key role for these molecules in initial development stages. In addition, NO2-Ln content increases significantly in stress situations and induces the expression of genes mainly related to abiotic stress, such as genes encoding members of the heat shock response family and antioxidant enzymes. The promoter regions of NO2-Ln-induced genes are also involved mainly in stress responses. These findings confirm that NO2-Ln is involved in plant defense processes against abiotic stress conditions via induction of the chaperone network and antioxidant systems. NO2-Ln signaling capacity lies mainly in its electrophilic nature and allows it to mediate a reversible post-translational modification called nitroalkylation, which is capable of modulating protein function. NO2-Ln is a NO donor that may be involved in NO signaling events and is able to generate S-nitrosoglutathione, the major reservoir of NO in cells and a key player in NO-mediated abiotic stress responses. This review describes the current state of the art regarding the essential role of nitro-fatty acids as signaling mediators in development and abiotic stress processes.

The Saccharomyces cerevisiae DNA repair gene RAD23 encodes a nuclear protein containing a ubiquitin-like domain required for biological function

1993 ◽  
Vol 13 (12) ◽  
pp. 7757-7765
Author(s):  
J F Watkins ◽  
P Sung ◽  
L Prakash ◽  
S Prakash
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Repair ◽  
Protein Function ◽  
Nuclear Protein ◽  
Biological Function ◽  
Excision Repair ◽  
Cellular Proteins ◽  
Repair Gene ◽  
Dna Repair Gene

In eukaryotes, the posttranslational conjugation of ubiquitin to various cellular proteins marks them for degradation. Interestingly, several proteins have been reported to contain ubiquitin-like (ub-like) domains that are in fact specified by the DNA coding sequences of the proteins. The biological role of the ub-like domain in these proteins is not known; however, it has been proposed that this domain functions as a degradation signal rendering the proteins unstable. Here, we report that the product of the Saccharomyces cerevisiae RAD23 gene, which is involved in excision repair of UV-damaged DNA, bears a ub-like domain at its amino terminus. This finding has presented an opportunity to define the functional significance of this domain. We show that deletion of the ub-like domain impairs the DNA repair function of RAD23 and that this domain can be functionally substituted by the authentic ubiquitin sequence. Surprisingly, RAD23 is highly stable, and the studies reported herein indicate that its ub-like domain does not mediate protein degradation. Thus, in RAD23 at least, the ub-like domain affects protein function in a nonproteolytic manner.

scholarly journals UPEC kidney infection triggers neuro-immune communication leading to modulation of local renal inflammation by splenic IFNγ

2021 ◽  
Vol 17 (5) ◽  
pp. e1009553
Author(s):  
Svava E. Steiner ◽  
Ferdinand X. Choong ◽  
Haris Antypas ◽  
Carlos E. Morado-Urbina ◽  
Anette Schulz ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Host Response ◽  
Host Responses ◽  
Renal Tubules ◽  
Host Pathogen Interaction ◽  
Inflammatory Signalling ◽  
Marginal Zones ◽  
Pharmaceutical Interventions

Bacterial infection results in a veritable cascade of host responses, both local and systemic. To study the initial stages of host-pathogen interaction in living tissue we use spatially-temporally controlled in vivo models. Using this approach, we show here that within 4 h of a uropathogenic Escherichia coli (UPEC) infection in the kidney, an IFNγ response is triggered in the spleen. This rapid infection-mediated inter-organ communication was found to be transmitted via nerve signalling. Bacterial expression of the toxin α-hemolysin directly and indirectly activated sensory neurons, which were identified in the basement membrane of renal tubules. Nerve activation was transmitted via the splenic nerve, inducing upregulation of IFNγ in the marginal zones of the spleen that led to increasing concentrations of IFNγ in the circulation. We found that IFNγ modulated the inflammatory signalling generated by renal epithelia cells in response to UPEC infection. This demonstrates a new concept in the host response to kidney infection; the role of nerves in sensing infection and rapidly triggering a systemic response which can modulate inflammation at the site of infection. The interplay between the nervous and immune systems is an exciting, developing field with the appealing prospect of non-pharmaceutical interventions. Our study identifies an important role for systemic neuro-immune communication in modulating inflammation during the very first hours of a local bacterial infection in vivo.

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