Drosophila lncRNA-NANPI enhances Toll signaling pathway by interacting with Dif/Dorsal to facilitate transcription of antibacterial peptides
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727845 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14459230_1.fastq.gz | Fastqsanger.gz | |||
| SRR14459230_2.fastq.gz | Fastqsanger.gz | |||
| SRR14459231_1.fastq.gz | Fastqsanger.gz | |||
| SRR14459231_2.fastq.gz | Fastqsanger.gz | |||
| SRR14459232_1.fastq.gz | Fastqsanger.gz |
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Project description:LncRNAs have important regulatory functions but their roles in Drosophila innate immunity are poorly understood. The Drosophila Toll signaling pathway responds to Gram-positive bacterial infection and is highly conserved with mammalian TLR signaling. Recent studies focused mainly on Toll signaling pathway regulation by protein-coding genes. In the present study, we found that lncRNA-CR33942 was upregulated after Micrococcus luteus infection. Gain-of-function and loss-of-function assays disclosed that lncRNA-CR33942 regulates the Toll signaling pathway and affects Drosophila survival. RNA-seq of infected CR33942-overexpressing flies was performed to explore the CR33942 mechanism. About 70% of all upregulated core enrichment genes in the Toll signaling pathway were antibacterial peptides and PGRPs transcribed by Dif/Dorsal. We also demonstrated CR33942 interactions with Dif/Dorsal and revealed that they induce antibacterial peptides. Hence, we renamed CR33942 as lncRNA-NANPI (NF-κB-associated non-coding RNA promotional immunology). The present study identified the novel Toll signaling pathway regulator NANPI, elucidated its mode of action, clarified the function of lncRNA, and expanded our understanding of the Toll signaling pathway.
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Project description:The maintenance of innate immune homeostasis is critical for animal survival to combat pathogens. Although many positive or negative protein factors have been identified, little is known about the long non-coding RNA that regulates the Toll pathway. Herein, we have discovered a novel lncRNA-CR11538 highly activated during the Drosophila response to gram+ bacterial infection. The transient overexpression of CR11538 inhibited the expression of antimicrobial peptides (Drosomycin and Metchnikowin) in vivo to suppress Toll signaling pathway. Remarkably, core enrichment genes based on RNAseq, subcellular localization and RIP suggest that CR11538 can interact with the transcription factor Dif/Dorsal in nucleus. ChIP-qPCR and dual luciferase report experiments show that CR11538 can sequester Dif/Dorsal away from the promoter thus suppressing the transcription of antimicrobial peptides. In summary, we discovered a novel lncRNA-CR11538 that negatively regulate the Drosophila Toll pathway. It broadens our understanding of the regulatory mechanism of Toll pathway involving lncRNA and provides insights for the research on innate immune system of insects and mammals.
2021-08-13 | GSE181870 | GEO
Project description:The Toll signaling pathway is highly conserved from insects to mammals. Drosophila is a model species that is commonly used to study innate immunity. Although many studies have assessed protein-coding genes that regulate the Toll pathway, it is unclear whether long noncoding RNAs (lncRNAs) play regulatory roles in the Toll pathway. Here, we evaluated the expression of the lncRNA CR46018 in Drosophila. Our results showed that this lncRNA was significantly overexpressed after infection of Drosophila with Micrococcus luteus. A CR46018-overexpressing Drosophila strain was then constructed; we expected that CR46018 overexpression would enhance the expression of various antimicrobial peptides downstream of the Toll pathway, regardless of infection with M. luteus. RNA-seq analysis of CR46018-overexpressing Drosophila after infection with M. luteus showed that upregulated genes were mainly enriched in Toll and Imd signaling pathways. Moreover, bioinformatics predictions and RNA-immunoprecipitation experiments showed that CR46018 interacted with the transcription factors Dif and Dorsal to enhance the Toll pathway. During gram-positive bacterial infection, flies overexpressing CR46018 showed favorable survival compared with flies in the control group. Based on these findings, we renamed CR46018 as lncRNA-RDIP. Overall, our current work not only reveals a new immune regulatory factor, lncRNA-RDIP, and explores its potential regulatory model, but also provides a new perspective for the effect of immune disorders on the survival of Drosophila melanogaster.
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Project description:lncRNA-CR46018 as a positive regulator controls Drosophila Toll immune response by interacting with Dif/Dorsal
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Project description:Obtaining an in depth understanding of the arms races between peptides comprising the innate immune response and bacterial pathogens is of fundamental interest and will inform the development of new antibacterial therapeutics. Many cationic antimicrobial peptides (AMPs) share a range of structural and physical features that have been linked to antibacterial activity and yet they vary dramatically in their potency towards the same bacterial target. We hypothesised that a whole organism view of AMP challenge on Escherichia coli could provide a sophisticated, bacterial perspective enabling understanding of how potency is linked to mode of action. We used a 1H NMR metabolomic approach to characterise the effect on E. coli of challenge with four structurally and physically related AMPs: magainin 2, pleurocidin, buforin II and a designed peptide comprising D-amino acids only. Sub-inhibitory conditions, where these peptides nevertheless induced a bacterial response, were identified enabling electron microscopic and transcriptomic analyses. Although some common features of the bacterial response to AMP challenge could be identified, the metabolomes, morphological changes and the vast majority of the changes in gene expression were specific to each AMP. We show the antibacterial mode of action of AMPs can be accurately predicted by comparing ontological profiles generated by transcriptomic analyses. The response of E. coli to AMP challenge is highly plastic, with the bacteria capable of deploying a multifaceted response adapted to the mode of action rather than the physical properties of the AMP.
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Project description:Cationic antimicrobial peptides (CAPs) are promising novel alternatives to conventional antibacterial agents, but the overlap in resistance mechanisms between small-molecule antibiotics and CAPs is unknown. Does evolution of antibiotic resistance decrease (cross-resistance) or increase (collateral sensitivity) susceptibility to CAPs? We systematically addressed this issue by studying the susceptibilities of a comprehensive set of antibiotic resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic resistant bacteria frequently showed collateral sensitivity to CAPs, while cross-resistance was relatively rare. We identified clinically relevant multidrug resistance mutations that simultaneously elevate susceptibility to certain CAPs. Transcriptome and chemogenomic analysis revealed that such mutations frequently alter the lipopolysaccharide composition of the outer cell membrane and thereby increase the killing efficiency of membrane-interacting antimicrobial peptides. Furthermore, we identified CAP-antibiotic combinations that rescue the activity of existing antibiotics and slow down the evolution of resistance to antibiotics. Our work provides a proof of principle for the development of peptide based antibiotic adjuvants that enhance antibiotic action and block evolution of resistance.
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