scholarly journals Circulating Metabolomic Signature in Generalized Pustular Psoriasis Blunts Monocyte Hyperinflammation by Triggering Amino Acid Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Ning Yu ◽  
Chen Peng ◽  
Wenjuan Chen ◽  
Ziwen Sun ◽  
Jianfeng Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
Amino Acid ◽  
Amino Acid Starvation ◽  
Pustular Psoriasis ◽  
Functional Assay ◽  
Dependent Manner ◽  
Blood Monocytes ◽  
Amyloid A ◽  
Generalized Pustular Psoriasis ◽  
Amino Acid Response

Generalized pustular psoriasis (GPP), the most grievous variant of psoriasis, is featured by dysregulated systemic inflammatory response. The cellular and molecular basis of GPP is poorly understood. Blood monocytes are key players of host defense and producers of inflammatory cytokines including IL-1β. How the immune response of monocytes is affected by metabolic internal environment in GPP remains unclear. Here, we performed a metabolomic and functional investigation of GPP serum and monocytes. We demonstrated a significant increase in IL-1β production from GPP monocytes. In GPP circulation, serum amyloid A (SAA), an acute-phase reactant, was dramatically increased, which induced the release of IL-1β from monocytes in a NLRP3-dependent manner. Using metabolomic analysis, we showed that GPP serum exhibited an amino acid starvation signature, with glycine, histidine, asparagine, methionine, threonine, lysine, valine, isoleucine, tryptophan, tyrosine, alanine, proline, taurine and cystathionine being markedly downregulated. In functional assay, under amino acid starvation condition, SAA-stimulated mature IL-1β secretion was suppressed. Mechanistically, at post-transcriptional level, amino acid starvation inhibited the SAA-mediated reactive oxygen species (ROS) formation and NLRP3 inflammasome activation. Moreover, the immune-modulatory effect of amino acid starvation was blocked by silencing general control nonderepressible 2 kinase (GCN2), suggesting the involvement of amino acid response (AAR) pathway. Collectively, our results suggested that decreased serum amino acids in GPP blunted the innate immune response in blood monocytes through AAR pathway, serving as a feedback mechanism preventing excessive inflammation in GPP.

scholarly journals Amino Acid Starvation Enhances Programmed Ribosomal Frameshift in Metavirus Ty3 of Saccharomyces cerevisiae

2016 ◽  
Vol 2016 ◽  
pp. 1-6
Author(s):  
Sezai Türkel
Keyword(s):  
Amino Acid ◽  
Amino Acid Starvation ◽  
Yeast Cells ◽  
Dependent Manner ◽  
Coding Region ◽  
Coding Regions ◽  
In The Wild ◽  
Amino Acid Depletion ◽  
A Site ◽  
Wild Type Yeast

Ty3 is a retroviral-like element and propagates with a retroviral-like mechanism within the yeast cells. Ty3 mRNA contains two coding regions, which are GAG3 and POL3. The coding region POL3 is translated as a GAG3-POL3 fusion protein by a +1 programmed frameshift. In this study, it was shown that the Ty3 frameshift frequency is significantly increased by amino acid starvation in a Gcn2p complex dependent manner. When the yeast cells were subjected to amino acid starvation, the frameshift frequency of Ty3 increased more than 2-fold in the wild-type yeast cells, mostly independent of Gcn4p. However, Ty3 frameshift frequency remained at basal level in the gcn1, gcn20, or gcn2 mutant yeast cells in amino acid starved yeasts. Gcn1p forms a complex with Gcn2p and Gcn20p and is involved in the sensing of uncharged tRNAs on the ribosomal A-site during translation. Increases in uncharged tRNA levels due to amino acid depletion lead to ribosomal pauses. These ribosomal pauses are significant actors in the regulation of Ty3 frameshift frequency. Results of this research revealed that frameshift frequency in Ty3 is regulated by the Gcn2p complex in response to amino acid starvation in yeast.

scholarly journals The Osmoregulatory and the Amino Acid-regulated Responses of System A Are Mediated by Different Signal Transduction Pathways

2003 ◽  
Vol 122 (1) ◽  
pp. 5-16 ◽  
Author(s):  
Marta López-Fontanals ◽  
Silvia Rodríguez-Mulero ◽  
F. Javier Casado ◽  
Benoit Dérijard ◽  
Marçal Pastor-Anglada
Keyword(s):  
Signal Transduction ◽  
Amino Acid ◽  
Adaptive Response ◽  
Amino Acid Starvation ◽  
Dominant Negative ◽  
Signal Transduction Pathways ◽  
Mrna Levels ◽  
Dependent Manner ◽  
System A ◽  
Osmotic Response

The osmotic response of system A for neutral amino acid transport has been related to the adaptive response of this transport system to amino acid starvation. In a previous study (Ruiz-Montasell, B., M. Gómez-Angelats, F.J. Casado, A. Felipe, J.D. McGivan, and M. Pastor-Anglada. 1994. Proc. Natl. Acad. Sci. USA. 91:9569–9573), a model was proposed in which both responses were mediated by different mechanisms. The recent cloning of several isoforms of system A as well as the elucidation of a variety of signal transduction pathways involved in stress responses allow to test this model. SAT2 mRNA levels increased after amino acid deprivation but not after hyperosmotic shock. Inhibition of p38 activity or transfection with a dominant negative p38 did not alter the response to amino acid starvation but partially blocked the hypertonicity response. Inhibition of the ERK pathway resulted in full inhibition of the adaptive response of system A and no increase in SAT2 mRNA levels, without modifying the response to hyperosmolarity. Similar results were obtained after transfection with a dominant negative JNK1. The CDK2 inhibitor peptide-II decreased the osmotic response in a dose-dependent manner but did not have any effect on the adaptive response of system A. In summary, the previously proposed model of up-regulation of system A after hypertonic shock or after amino acid starvation by separate mechanisms is now confirmed and the two signal transduction pathways have been identified. The involvement of a CDK–cyclin complex in the osmotic response of system A links the activity of this transporter to the increase in cell volume previous to the entry in a new cell division cycle.

scholarly journals Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals

2009 ◽  
Vol 29 (24) ◽  
pp. 6515-6526 ◽  
Author(s):  
Cédric Chaveroux ◽  
Céline Jousse ◽  
Yoan Cherasse ◽  
Anne-Catherine Maurin ◽  
Laurent Parry ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Amino Acid ◽  
Signal Transduction Pathway ◽  
Amino Acid Starvation ◽  
Mitogen Activated Protein Kinase ◽  
Individual Gene ◽  
Amino Acid Availability ◽  
Rna Transfection ◽  
Mitogen Activated Protein ◽  
Amino Acid Response

ABSTRACT It has been well established that amino acid availability can control gene expression. Previous studies have shown that amino acid depletion induces transcription of the ATF3 (activation transcription factor 3) gene through an amino acid response element (AARE) located in its promoter. This event requires phosphorylation of activating transcription factor 2 (ATF2), a constitutive AARE-bound factor. To identify the signaling cascade leading to phosphorylation of ATF2 in response to amino acid starvation, we used an individual gene knockdown approach by small interfering RNA transfection. We identified the mitogen-activated protein kinase (MAPK) module MEKK1/MKK7/JNK2 as the pathway responsible for ATF2 phosphorylation on the threonine 69 (Thr69) and Thr71 residues. Then, we progressed backwards up the signal transduction pathway and showed that the GTPase Rac1/Cdc42 and the protein Gα12 control the MAPK module, ATF2 phosphorylation, and AARE-dependent transcription. Taken together, our data reveal a new signaling pathway activated by amino acid starvation leading to ATF2 phosphorylation and subsequently positively affecting the transcription of amino acid-regulated genes.

scholarly journals Imiquimod Treatment Causes Systemic Disease in Mice Resembling Generalized Pustular Psoriasis in an IL-1 and IL-36 Dependent Manner

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Pilar Alvarez ◽  
Liselotte E. Jensen
Keyword(s):  
Mouse Model ◽  
Inflammatory Mediators ◽  
Plaque Psoriasis ◽  
Systemic Disease ◽  
Severe Disease ◽  
Skin Inflammation ◽  
Pustular Psoriasis ◽  
Dependent Manner ◽  
Missense Mutations ◽  
Generalized Pustular Psoriasis

Generalized pustular psoriasis (GPP) is a severe form of psoriasis that can be caused by missense mutations in the interleukin-36 (IL-36) receptor antagonist. In addition to neutrophil rich skin inflammation, GPP patients typically also experience anorexia, fever, malaise, and pain. The imiquimod-induced skin inflammation mouse model has rapidly become a popular way to study plaque psoriasis, which typically does not involve symptoms of systemic disease. In this model, neutrophil recruitment to the skin is dependent upon the inflammatory mediators IL-1, via its receptor IL-1R1, and IL-36α. Unexpectedly, we observed that mice also exhibited signs of anorexia (weight loss and decreased food intake), general malaise (decreased activity and loss of interest in building nests), and pain (nose bulging and hunched posture). A scoring system allowing quantitative comparisons of test groups was developed. Female mice were found to develop more severe disease than male mice. Furthermore, mice deficient in both IL-1R1 and IL-36α are nearly disease-free, while mice lacking only one of these inflammatory mediators have less severe disease than wild type mice. Hence, the imiquimod-induced skin inflammation mouse model recapitulates not only plaque psoriasis, but also the more severe symptoms, that is, anorexia, malaise, and pain, seen in GPP.

scholarly journals Engineering RNA viruses with unnatural amino acid to evoke adjustable immune response in mice

2021 ◽  
Author(s):  
Zhetao Zheng ◽  
Yu Wang ◽  
Xuesheng Wu ◽  
Haoran Zhang ◽  
Hongmin Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Amino Acid ◽  
Genetic Code ◽  
Rna Viruses ◽  
Enterovirus 71 ◽  
Unnatural Amino Acid ◽  
Dependent Manner ◽  
Strong Immune Response ◽  
Genetic Code Expansion ◽  
Dose Dependent

Ribonucleic acid (RNA) viruses pose heavy burdens on public-health systems. Synthetic biology holds great potential for artificially controlling their replication, a strategy that could be used to attenuate infectious viruses but is still in the exploratory stage. Herein, we used the genetic-code expansion technique to convert Enterovirus 71 (EV71), a model of RNA virus, into a controllable EV71 strain carrying the unnatural amino acid (UAA) Nε-2-azidoethyloxycarbonyl-L-lysine (NAEK), which we termed an EV71-NAEK virus. EV71-NAEK could recapitulate an authentic NAEK time- and dose-dependent infection in vitro and in vivo, which could serve as a novel method to manipulate virulent viruses in conventional laboratories. We further validated the prophylactic effect of EV71-NAEK in two mouse models. In susceptible parent mice, vaccination with EV71-NAEK elicited a strong immune response and potentially protected their neonatal offspring from lethal challenge similar to that of commercial vaccines. Meanwhile, in transgenic mice harboring a PylRS-tRNAPyl CUA pair, substantial elements of genetic-code expansion technology, EV71-NAEK evoked an adjustable neutralizing-antibody response in a strictly external NAEK dose-dependent manner. These findings suggested that EV71-NAEK could be the basis of a feasible immunization program for populations with different levels of immunity. Moreover, we expanded the strategy to generate controllable coxsackieviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for conceptual verification. In combination, these results could underlie a competent strategy for attenuating viruses and priming the immune system via artificial control, which might be a promising direction for the development of amenable vaccine candidates and be broadly applied to other RNA viruses.

scholarly journals General amino acid control in fission yeast is regulated by a nonconserved transcription factor, with functions analogous to Gcn4/Atf4

2018 ◽  
Vol 115 (8) ◽  
pp. E1829-E1838 ◽  
Author(s):  
Caia D. S. Duncan ◽  
María Rodríguez-López ◽  
Phil Ruis ◽  
Jürg Bähler ◽  
Juan Mata
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Amino Acid ◽  
Fission Yeast ◽  
Transcriptional Response ◽  
Amino Acid Starvation ◽  
Ribosome Profiling ◽  
Transcriptional Networks ◽  
Dependent Manner ◽  
Zip Family

Eukaryotes respond to amino acid starvation by enhancing the translation of mRNAs encoding b-ZIP family transcription factors (GCN4 in Saccharomyces cerevisiae and ATF4 in mammals), which launch transcriptional programs to counter this stress. This pathway involves phosphorylation of the eIF2 translation factor by Gcn2-protein kinases and is regulated by upstream ORFs (uORFs) in the GCN4/ATF4 5′ leaders. Here, we present evidence that the transcription factors that mediate this response are not evolutionarily conserved. Although cells of the fission yeast Schizosaccharomyces pombe respond transcriptionally to amino acid starvation, they lack clear Gcn4 and Atf4 orthologs. We used ribosome profiling to identify mediators of this response in S. pombe, looking for transcription factors that behave like GCN4. We discovered a transcription factor (Fil1) translationally induced by amino acid starvation in a 5′ leader and Gcn2-dependent manner. Like Gcn4, Fil1 is required for the transcriptional response to amino acid starvation, and Gcn4 and Fil1 regulate similar genes. Despite their similarities in regulation, function, and targets, Fil1 and Gcn4 belong to different transcription factor families (GATA and b-ZIP, respectively). Thus, the same functions are performed by nonorthologous proteins under similar regulation. These results highlight the plasticity of transcriptional networks, which maintain conserved principles with nonconserved regulators.

scholarly journals Class III phosphoinositide 3-kinase–Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes

2003 ◽  
Vol 376 (3) ◽  
pp. 577-586 ◽  
Author(s):  
Amina TASSA ◽  
Marie Paule ROUX ◽  
Didier ATTAIX ◽  
Daniel M. BECHET
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Amino Acid Starvation ◽  
Class I ◽  
C2c12 Myotubes ◽  
Dependent Manner ◽  
Class Iii ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Increased proteolysis contributes to muscle atrophy that prevails in many diseases. Elucidating the signalling pathways responsible for this activation is of obvious clinical importance. Autophagy is a ubiquitous degradation process, induced by amino acid starvation, that delivers cytoplasmic components to lysosomes. Starvation markedly stimulates autophagy in myotubes, and the present studies investigate the mechanisms of this regulation. In C2C12 myotubes incubated with serum growth factors, amino acid starvation stimulated autophagic proteolysis independently of p38 and p42/p44 mitogen-activated protein kinases, but in a PI3K (phosphoinositide 3-kinase)-dependent manner. Starvation, however, did not alter activities of class I and class II PI3Ks, and was not sufficient to affect major signalling proteins downstream from class I PI3K (glycogen synthase kinase, Akt/protein kinase B and protein S6). In contrast, starvation increased class III PI3K activity in whole-myotube extracts. In fact, this increase was most pronounced for a population of class III PI3K that coimmunoprecipitated with Beclin1/Apg6 protein, a major determinant in the initiation of autophagy. Stimulation of proteolysis was reproduced by feeding myotubes with synthetic dipalmitoyl-PtdIns3P, the class III PI3K product. Conversely, protein transfection of anti-class III PI3K inhibitory antibody into starved myotubes inverted the induction of proteolysis. Therefore, independently of class I PI3K/Akt, protein S6 and mitogen-activated protein kinase pathways, amino acid starvation stimulates proteolysis in myotubes by regulating class III PI3K–Beclin1 autophagic complexes.

scholarly journals Receptor Binding by Cholera Toxin B-Subunit and Amino Acid Modification Improves Minimal Peptide Immunogenicity

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
Andreas Boberg ◽  
Alexandra Stålnacke ◽  
Andreas Bråve ◽  
Jorma Hinkula ◽  
Britta Wahren ◽  
...  
Keyword(s):  
Immune Response ◽  
Amino Acid ◽  
Cholera Toxin ◽  
Cellular Immune Response ◽  
Binding Capacity ◽  
Functional Assay ◽  
Cholera Toxin B Subunit ◽  
Acid Modification ◽  
B Subunit ◽  
Cellular Immune

We increase our understanding of augmenting a cellular immune response, by using an HIV-1 protease-derived epitope (PR75–84), and variants thereof, coupled to the C-terminal, of the B subunit of cholera toxin (CTB). Fusion proteins were used for immunizations of HLA-A0201 transgenic C57BL/6 mice. We observed different capacities to elicit a cellular immune response by peptides with additions of five to ten amino acids to the PR epitope. There was a positive correlation between the magnitude of the elicited cellular immune response and the capacity of the fusion protein to bind GM-1. This binding capacity is affected by its ability to form natural pentamers of CTB. Our results suggest that functional CTB pentamers containing a foreign amino acid-modified epitope is a novel way to overcome the limited cellular immunogenicity of minimal peptide antigens. This way of using a functional assay as readout for improved cellular immunogenicity might become highly valuable for difficult immunogens such as short peptides (epitopes).

scholarly journals Role of Bacterial Lipopolysaccharide in Enhancing Host Immune Response toCandida albicans

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Helen Rogers ◽  
David W. Williams ◽  
Gui-Jie Feng ◽  
Michael A. O. Lewis ◽  
Xiao-Qing Wei
Keyword(s):  
Immune Response ◽  
Human Peripheral Blood ◽  
Cell Receptor ◽  
Bacterial Lipopolysaccharide ◽  
Dependent Manner ◽  
Blood Monocytes ◽  
Gm Csf ◽  
A Cell ◽  
Human Infections

Human infections involving yeast of the genusCandidaoften occur in the presence of bacteria, and, as such, it is important to understand how these bacteria influence innate host immunity towardsCandida. Dectin-1 is a cell receptor of macrophages forCandida albicansrecognition. The aim of this study was to examine dectin-1 expression by monocytes after stimulation with bacterial lipopolysaccharide (LPS), followed by heat-killedC. albicans(HKC). Freshly isolated human peripheral blood monocytes (PBMCs) and human monocytes cell line (THP-1) cells expressed low levels of dectin-1. Stimulation with LPS and GM-CSF/IL-4 was found to increase dectin-1 expression in both CD14+human PBMC and THP-1 cells. Enhanced dectin-1 expression resulted in increased phagocytosis ofCandida. When THP-1 cells were challenged only with HKC, detectable levels of IL-23 were not evident. However, challenge by LPS followed by varying concentrations of HKC resulted in increased IL-23 expression by THP-1 cells in HKC dose-dependent manner. Increased expression of IL-17 by PBMC also occurred after stimulation withCandidaand LPS. In conclusion, bacterial LPS induces an enhanced immune response toCandidaby immune cells, and this occurs through increasing dectin-1 expression.

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