The circular RNA Edis regulates neurodevelopment and innate immunity

Abstract

Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset has been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis (circ_Ect4) causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotor activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Furthermore, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain. Moreover, we provide evidence that Edis encodes a functional protein that associates with and compromises the processing and activation of the immune transcription factor Relish. Importantly, restoring Edis expression or ectopic expression of Edis-encoded protein suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. Thus, our study establishes Edis as a key regulator of neurodevelopment and innate immunity.

A circular RNA Edis-Relish-castor axis regulates neuronal development in Drosophila

“…Among the tissues/organs examined, including hemocytes, salivary gland, gut, body wall muscle, and fat body, Edis was most prominently enriched in the brain ( Fig 1A ). This is consistent with the notion that circRNAs are enriched in the nervous system [ 22 , 23 , 39 ]. To further visualize the localization pattern of Edis within the brain, RNA fluorescence in situ hybridization assay was performed.…”

“…In addition, we crossed Elav-Gal4 with UAS-laccase2-Edis flies to drive Edis expression in neurons. We find that restoring Edis expression can rescue the neurodevelopmental phenotypes elicited by Edis knockdown [ 39 ], thereby demonstrating the functional relevance of overexpressed Edis . We therefore employed a similar experimental setting to examine whether overexpressed Edis impacts neuronal development.…”

“…Recently, we show that overexpression of Edis suppressed the IMD innate immunity signaling pathway both in cultured cells and in vivo [ 39 ]. In addition, we crossed Elav-Gal4 with UAS-laccase2-Edis flies to drive Edis expression in neurons.…”

“…Glial cells are an integral component of the nervous system and interact extensively with neurons. Our recent study reveals that Edis is expressed in glia [ 39 ]. We therefore depleted Edis in glial cells using Repo-Gal4 [ 53 ].…”

“…In a recent study, we describe the identification and functional characterization a circRNA circEct4 , also known as Edis ( Ect4-derived immune suppressor ) [ 39 ]. Knockdown of Edis , but not its linear sibling Ect4 , specifically in neurons causes hyperactivation of innate immunity and myriad defects in neuronal development.…”