Abstract
Avoiding excessive or insufficient immune responses and maintaining homeostasis are critical for animal survival. Although many positive or negative modulators involved in immune responses have been identified, little has been reported to date concerning whether the long non-coding RNA (lncRNA) can regulate Drosophila immunity response. In this study, we firstly discover that the overexpression of lncRNA-CR11538 can inhibit the expressions of antimicrobial peptides Drosomycin (Drs) and Metchnikowin (Mtk) in vivo, thereby suppressing the Toll signaling pathway. Secondly, our results demonstrate that lncRNA-CR11538 can interact with transcription factors Dif/Dorsal in the nucleus based on both subcellular localization and RIP analyses. Thirdly, our findings reveal that lncRNA-CR11538 can decoy Dif/Dorsal away from the promoters of Drs and Mtk to repress their transcriptions by ChIP-qPCR and dual luciferase report experiments. Fourthly, the dynamic expression changes of Drs, Dif, Dorsal and lncRNA-CR11538 in wild-type flies (w1118) at different time points after M. luteus stimulation disclose that lncRNA-CR11538 can help Drosophila restore immune homeostasis in the later period of immune response. Overall, our study reveals a novel mechanism by which lncRNA-CR11538 serves as a Dif/Dorsal decoy to downregulate antimicrobial peptide expressions for restoring Drosophila Toll immunity homeostasis, and provides a new insight into further studying the complex regulatory mechanism of animal innate immunity.
Highlights
The innate immune system can effectively protect animals from various bacteria, fungi and other pathogens [1,2,3]
To explore whether long noncoding RNA (lncRNA)-CR11538 can participate in the regulation of Drosophila immunity responses, we constructed the CR11538overexpressing flies using the pUAST-attB plasmid method, and confirmed that lncRNACR11538 was successfully constructed to the desired position in Drosophila genome (Figure 1B)
To overexpress Drosophila lncRNA-CR11538 in a specific period of time, these overexpressing lncRNA-CR11538 transgenic flies were transiently driven by a temperature sensitive Tub-Gal80ts; Tub-Gal4 flies were especially influenced; the expression level of lncRNA-CR11538 was about 400 times higher than the control (Figure 1C)
Summary
The innate immune system can effectively protect animals from various bacteria, fungi and other pathogens [1,2,3]. The Toll signaling pathway goes through a series of signaling cascades to induce NF-κB transcription factor Dif/Dorsal into the nucleus to activate the expressions of antimicrobial peptides (AMPs) in response to Gram-positive bacteria or fungal invasion in Drosophila [5,6]. Many non-coding RNAs, such as miRNAs, can negatively regulate innate immune response of Toll signaling pathway [19,20,21,22,23,24], little is known about the regulatory role of long non-coding RNAs (lncRNAs) in the Drosophila Toll signaling pathway, and further study is needed. The nucleus-localized lncRNA can participate in regulating the binding of transcription factors to gene promoter regions at the transcription level or modulating epigenetic factors, which has been well studied in mammals [28]. LncRNA-CCND1 can repress CCND1 transcription by recruiting TLS to the promoter of CCND1 [30]
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