scholarly journals Co-option of immune effectors by the hormonal signalling system triggering metamorphosis in Drosophila melanogaster

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009916
Author(s):  
Catarina Nunes ◽  
Takashi Koyama ◽  
Élio Sucena
Keyword(s):  
Drosophila Melanogaster ◽  
Fat Body ◽  
Developmental Regulation ◽  
Bacterial Load ◽  
Systemic Effect ◽  
Dependent Manner ◽  
Downstream Target ◽  
Local Responses ◽  
Insect Metamorphosis

Insect metamorphosis is triggered by the production, secretion and degradation of 20-hydroxyecdysone (ecdysone). In addition to its role in developmental regulation, increasing evidence suggests that ecdysone is involved in innate immunity processes, such as phagocytosis and the induction of antimicrobial peptide (AMP) production. AMP regulation includes systemic responses as well as local responses at surface epithelia that contact with the external environment. At pupariation, Drosophila melanogaster increases dramatically the expression of three AMP genes, drosomycin (drs), drosomycin-like 2 (drsl2) and drosomycin-like 5 (drsl5). We show that the systemic action of drs at pupariation is dependent on ecdysone signalling in the fat body and operates via the ecdysone downstream target, Broad. In parallel, ecdysone also regulates local responses, specifically through the activation of drsl2 expression in the gut. Finally, we confirm the relevance of this ecdysone dependent AMP expression for the control of bacterial load by showing that flies lacking drs expression in the fat body have higher bacterial persistence over metamorphosis. In contrast, local responses may be redundant with the systemic effect of drs since reduction of ecdysone signalling or of drsl2 expression has no measurable negative effect on bacterial load control in the pupa. Together, our data emphasize the importance of the association between ecdysone signalling and immunity using in vivo studies and establish a new role for ecdysone at pupariation, which impacts developmental success by regulating the immune system in a stage-dependent manner. We speculate that this co-option of immune effectors by the hormonal system may constitute an anticipatory mechanism to control bacterial numbers in the pupa, at the core of metamorphosis evolution.

scholarly journals Co-option of local and systemic immune responses by the hormonal signalling system triggering metamorphosis

2021 ◽  
Author(s):  
Catarina Nunes ◽  
Takashi Koyama ◽  
Elio Sucena
Keyword(s):  
Immune Responses ◽  
Fat Body ◽  
Developmental Regulation ◽  
Bacterial Persistence ◽  
Systemic Immune Response ◽  
Downstream Target ◽  
Local Responses ◽  
Insect Metamorphosis ◽  
Systemic Responses ◽  
Hormonal Signalling

Insect metamorphosis is regulated by the production, secretion and degradation of two peripheral hormones: 20-hydroxyecdysone (ecdysone) and juvenile hormone (JH). In addition to their roles in developmental regulation, increasing evidence suggests that these hormones are involved in innate immunity processes, such as phagocytosis and the induction of antimicrobial peptide (AMP) production. AMP regulation includes systemic responses and local responses, at surface epithelia that contact with the external environments. At pupariation, Drosophila melanogaster increases dramatically the expression of three AMP genes: drosomycin (drs), drosomycin-like 2 (drsl2) and drosomycin-like 5 (drsl5). Using D. melanogaster, we show that the expression of drs at pupariation is dependent on ecdysone signalling in the fat body. This systemic immune response involving drs expression in the fat body operates via the ecdysone downstream target, Broad-Z4. In parallel, ecdysone also regulates local responses, specifically through the activation of drsl2 expression in the gut. Finally, we establish the relevance of this ecdysone dependent AMP expression for the control of bacterial persistence by showing that flies lacking drs expression in the fat body have higher bacterial persistence over metamorphosis. Together, our data establishes a new role for ecdysone during pupariation. We propose that the co-option of immune mechanisms by the hormonal cascade responsible for controlling metamorphosis constitutes a pre-emptive mechanism to control bacterial numbers in the pupa and increase developmental success.

Recent findings on oogenesis of Drosophila melanogaster

Development ◽  
1977 ◽  
Vol 38 (1) ◽  
pp. 125-138
Author(s):  
F. Giorgi ◽  
J. Jacob
Keyword(s):  
Drosophila Melanogaster ◽  
Fat Body ◽  
Radioactive Tracer ◽  
Superficial Layer ◽  
Ruthenium Red ◽  
Time Interval ◽  
Intracellular Location ◽  
Short Time

Vitellogenic ovaries from Drosophila melanogaster flies have been exposed, either in in vivo or in vitro conditions, to various extracellular tracers in an attempt to determine the possible route of entry of the yolk precursors. Ruthenium red and lanthanum nitrate have been shown to gain access to the oocyte surface by initially passing through the intercellular spaces of the follicle layer. Both these tracers, however, never attain an intracellular location within any of the cells forming the ovarian chamber. Colloidal Thorotrast when injected into adult females has never been detected within any of the ovarian chambers examined, irrespective of their stage. Vitellogenic oocytes exposed to peroxidase in in vivo conditions exhibit the oolemma and all the structural elements present in the cortical ooplasm well labelled within a very short time after the injection. Moreover, with gradually increasing exposure times to peroxidase, the labelled yolk platelets increase progressively in number. At each time interval after the injection, the label over the yolk platelets remains restricted to the superficial layer and never gets into the associated body. The pattern of tritiated lysine incorporation into vitellogenic oocytes has been studied over a period of 20 h. A few hours after injection of the radioactive tracer, the silver grains located over the ooplasm appear distributed at random. A predominant labelling of the yolk platelets as compared to the rest of the ooplasm, becomes evident only with a 6 h delay since the time of injection. When analysed by electrophoresis and isolectrofocusing, the vitellogenic ovary is seen to exhibit a number of protein bands which are common to those of other tissues as, for instance, haemolymph and fat body. The evidence obtained in the present study is discussed in relation to the hypothesis of an extraovarian origin of the yolk precursors and their sequestration into forming yolk platelets.

scholarly journals Tissue-Specific Regulation of Drosophila NF-κB Pathway Activation by Peptidoglycan Recognition Protein SC

2015 ◽  
Vol 8 (1) ◽  
pp. 67-80 ◽  
Author(s):  
Denis Costechareyre ◽  
Florence Capo ◽  
Alexandre Fabre ◽  
Delphine Chaduli ◽  
Christine Kellenberger ◽  
...  
Keyword(s):  
Fat Body ◽  
Bacterial Load ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Peptidoglycan Recognition Protein ◽  
Imd Pathway ◽  
Pathway Activation ◽  
Recognition Protein ◽  
Specific Regulation

In Drosophila, peptidoglycan (PGN) is detected by PGN recognition proteins (PGRPs) that act as pattern recognition receptors. Some PGRPs such as PGRP-LB or PGRP-SCs are able to cleave PGN, therefore reducing the amount of immune elicitors and dampening immune deficiency (IMD) pathway activation. The precise role of PGRP-SC is less well defined because the PGRP-SC genes (PGRP-SC1a, PGRP-SC1b and PGRP-SC2) lie very close on the chromosome and have been studied using a deletion encompassing the three genes. By generating PGRP-SC-specific mutants, we reevaluated the roles of PGRP-LB, PGRP-SC1 and PGRP-SC2, respectively, during immune responses. We showed that these genes are expressed in different gut domains and that they follow distinct transcriptional regulation. Loss-of-function mutant analysis indicates that PGRP-LB is playing a major role in IMD pathway activation and bacterial load regulation in the gut, although PGRP-SCs are expressed at high levels in this organ. We also demonstrated that PGRP-SC2 is the main negative regulator of IMD pathway activation in the fat body. Accordingly, we showed that mutants for either PGRP-LB or PGRP-SC2 displayed a distinct susceptibility to bacteria depending on the infection route. Lastly, we demonstrated that PGRP-SC1 and PGRP-SC2 are required in vivo for full Toll pathway activation by Gram-positive bacteria.

scholarly journals The ecdysone response enhancer of the Fbp1 gene of Drosophila melanogaster is a direct target for the EcR/USP nuclear receptor.

1994 ◽  
Vol 14 (7) ◽  
pp. 4465-4474 ◽  
Author(s):  
C Antoniewski ◽  
M Laval ◽  
A Dahan ◽  
J A Lepesant
Keyword(s):  
Drosophila Melanogaster ◽  
Binding Site ◽  
Fat Body ◽  
Sequence Similarity ◽  
High Concentration ◽  
Direct Role ◽  
Palindromic Structure ◽  
Fbp1 Gene

The transcription of the Drosophila melanogaster Fbp1 gene is induced by the steroid hormone 20-hydroxyecdysone and restricted to the late-third-instar fat body tissue. In a previous study we showed that the -68 to -138 region relative to the transcription start site acts as an ecdysone-dependent third-instar fat body-specific enhancer in a transgenic assay. Here we report that seven nucleoprotein complexes are formed in vitro on this enhancer when a nuclear extract from late-third-instar fat body is used in a gel shift assay. Accurate mapping of the binding sites of the complexes revealed a remarkably symmetrical organization. Using specific antibodies, one of the complexes was identified as a heterodimer consisting of the ecdysone receptor (EcR) and Ultraspiracle (USP) proteins. The binding site of the heterodimer as defined by mutagenesis and methylation interference experiments bears strong sequence similarity to the canonical hsp27 ecdysone response element, including an imperfect palindromic structure. The two elements diverge at three positions in both half-sites, indicating that the structure of an active EcR/USP binding site allows considerable sequence variations. In vivo footprinting experiments using ligation-mediated PCR and wild-type or ecdysteroid-deficient larvae show that occupancy of the Fbp1 EcR/USP binding site and adjacent region is dependent on a high concentration of ecdysteroids. These results provide strong evidence for a direct role of the EcR/USP heterodimer in driving gene expression in response to changes of the ecdysteroid titer during Drosophila larval development.

scholarly journals Amaranth Leaf Extract Protects Against Hydrogen Peroxide Induced Oxidative Stress in Drosophila Melanogaster

2021 ◽  
Author(s):  
Johnmark Ndinawe ◽  
Hellen W. Kinyi
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Antioxidant Activity ◽  
Ascorbic Acid ◽  
Drosophila Melanogaster ◽  
Leaf Extract ◽  
Dependent Manner ◽  
Polyphenol Compounds ◽  
Dose Dependent

Abstract ObjectiveAmaranths leaves are rich in ascorbic acid and polyphenol compounds which have antioxidant activity. The aim of this study was to evaluate their in vivo antioxidant activity. The effect of consumption of Amaranth leaf extract on in vivo antioxidant activity, catalase enzyme activity and H2O2 induced oxidative stress in Drosophila melanogaster flies was assessed.ResultsConsumption of Amaranth leaf extract was associated with increased survival on exposure to H202 in a dose dependent manner in Drosophila melanogaster flies.

scholarly journals TCF4 and HuR Mediated-METTL14 Suppresses Dissemination of Colorectal Cancer via N6-Methyladenosine-Dependent Silencing of ARRDC4

2021 ◽  
Author(s):  
Hao Wang ◽  
Wei Wei ◽  
Zhong-Yuan Zhang ◽  
Yao Liu ◽  
Bin Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chromatin Immunoprecipitation ◽  
Dependent Manner ◽  
Dot Blot ◽  
Downstream Target ◽  
In Vivo Assays ◽  
Rna Immunoprecipitation ◽  
Underlying Mechanisms

Abstract Background: Metastasis remains the major obstacle to improved survival for colorectal cancer (CRC) patients. Dysregulation of N6-methyladenosine (m6A) is causally associated with the development of metastasis through poorly understood mechanisms. Methods: The expression of METTL14 and its correlation with clinicopathological features were evaluated by western blot and immunohistochemistry. The roles of METTL14 in CRC metastasis were determined through in vitro and in vivo assays. The underlying mechanisms of METTL14 regulation were explored using transcriptome-sequencing, m6A-seguencing, methylated RNA immunoprecipitation (MeRIP), m6A dot blot, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assay.Results: METTL14 is functionally related to the inhibition of ARRDC4/ZEB1 signaling and to the consequent suppression of CRC metastasis. We unveil METTL14-mediated m6A modification profile and identify ARRDC4 as a direct downstream target of METTL14. Knockdown of METTL14 significantly enhances ARRDC4 mRNA stability relying on the “reader” protein YHTDF2 dependent manner. Moreover, TCF4 can induce METTL14 protein expression, and HuR suppresses METTL14 expression by directly binding to its promoter. Clinically, decreased METTL14 is correlated with poor prognosis and acts as an independent predictor of CRC survival. Conclusion: Our data suggest that TCF4 and HuR mediated-METTL14 can trigger the metastasis of CRC during cancer development via YHTDF2/ARRDC4/ZEB1 axis, which imposes great challenge that inhibition of METTL14 is a potential approach for cancer treatment.

scholarly journals Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9

Blood ◽  
2020 ◽  
Author(s):  
Seiko Yoshino ◽  
Takashi Yokoyama ◽  
Yoshitaka Sunami ◽  
Tomoko Takahara ◽  
Aya Nakamura ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genetic Effect ◽  
Dependent Manner ◽  
Enhancer Activity ◽  
Downstream Target ◽  
Erk Phosphorylation ◽  
Acute Myeloid

The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPa and interacts with MEK1 to enhance ERK phosphorylation. Close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased mRNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPa p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

Pelle kinase is activated by autophosphorylation during Toll signaling in Drosophila

Development ◽  
2002 ◽  
Vol 129 (8) ◽  
pp. 1925-1933 ◽  
Author(s):  
Baohe Shen ◽  
James L. Manley
Keyword(s):  
Dependent Manner ◽  
Loss Of Function ◽  
Concentration Dependent Manner ◽  
Downstream Target ◽  
Toll Signaling ◽  
Early Embryos ◽  
High Concentrations ◽  
L2 Cells

The Drosophila Pelle kinase plays a key role in the evolutionarily conserved Toll signaling pathway, but the mechanism responsible for its activation has been unknown. We present in vivo and in vitro evidence establishing an important role for concentration-dependent autophosphorylation in the signaling process. We first show that Pelle phosphorylation can be detected transiently in early embryos, concomitant with activation of signaling. Importantly, Pelle phosphorylation is enhanced in a gain-of-function Toll mutant (Toll10b), but decreased by loss-of-function Toll alleles. Next we found that Pelle is phosphorylated in transfected Schneider L2 cells in a concentration-dependent manner such that significant modification is observed only at high Pelle concentrations, which coincide with levels required for phosphorylation and activation of the downstream target, Dorsal. Pelle phosphorylation is also enhanced in L2 cells co-expressing Toll10b, and is dependent on Pelle kinase activity. In vitro kinase assays revealed that recombinant, autophosphorylated Pelle is far more active than unphosphorylated Pelle. Importantly, unphosphorylated Pelle becomes autophosphorylated, and activated, by incubation at high concentrations. We discuss these results in the context of Toll-like receptor mediated signaling in both flies and mammals.

scholarly journals Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

2005 ◽  
Vol 49 (6) ◽  
pp. 2294-2301 ◽  
Author(s):  
Anne J. Lenaerts ◽  
Veronica Gruppo ◽  
Karen S. Marietta ◽  
Christine M. Johnson ◽  
Diane K. Driscoll ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Significant Activity ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Long Term Treatment

ABSTRACT This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 μg/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 μg/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

scholarly journals The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila

2010 ◽  
Vol 30 (10) ◽  
pp. 2485-2497 ◽  
Author(s):  
Hans-Martin Herz ◽  
Laurence D. Madden ◽  
Zhihong Chen ◽  
Clare Bolduc ◽  
Eugene Buff ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Histone H3 ◽  
Epigenetic Mark ◽  
Dependent Manner ◽  
Wild Type ◽  
Independent Manner ◽  
Jmjc Domain ◽  
Mutant Cells ◽  
Excessive Activation

ABSTRACT Trimethylated lysine 27 of histone H3 (H3K27me3) is an epigenetic mark for gene silencing and can be demethylated by the JmjC domain of UTX. Excessive H3K27me3 levels can cause tumorigenesis, but little is known about the mechanisms leading to those cancers. Mutants of the Drosophila H3K27me3 demethylase dUTX display some characteristics of Trithorax group mutants and have increased H3K27me3 levels in vivo. Surprisingly, dUTX mutations also affect H3K4me1 levels in a JmjC-independent manner. We show that a disruption of the JmjC domain of dUTX results in a growth advantage for mutant cells over adjacent wild-type tissue due to increased proliferation. The growth advantage of dUTX mutant tissue is caused, at least in part, by increased Notch activity, demonstrating that dUTX is a Notch antagonist. Furthermore, the inactivation of Retinoblastoma (Rbf in Drosophila) contributes to the growth advantage of dUTX mutant tissue. The excessive activation of Notch in dUTX mutant cells leads to tumor-like growth in an Rbf-dependent manner. In summary, these data suggest that dUTX is a suppressor of Notch- and Rbf-dependent tumors in Drosophila melanogaster and may provide a model for UTX-dependent tumorigenesis in humans.

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