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The Circular RNA Edis Regulates Neurodevelopment and Innate Immunity

ABSTRACT: Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset have been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis 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 locomotive activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Importantly, restoration of Edis expression suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. We provide evidence that Edis encodes a functional protein that associates with and compromises the processing of the immune transcription factor Relish. Consistent with these observations, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain and rescues the neurodevelopment defects in Edis knockdown neurons. Thus, our study establishes the circRNA Edis as a key regulator of neurodevelopment and innate immunity.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE188484 | GEO | 2022/10/04

REPOSITORIES: GEO

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

Project description:Circular RNAs (circRNAs) are a new group of noncoding and regulatory RNAs that are particularly abundant in the nervous system, although their physiological functions are underexplored. Here we report that the brain-enriched circular RNA Edis (Ect4-derived immune suppressor) plays an essential role in neuronal development in Drosophila, as its depletion causes defective axonal projection of mushroom body (MB) neurons in the brain, as well as impaired locomotor activity and shortened lifespan of adult flies. In addition, we show that the castor gene, which encodes a transcription factor involved in neurodevelopment, is upregulated in Edis knockdown neurons. Notably, castor overexpression phenocopies Edis knockdown, and reducing castor levels suppresses the neuronal developmental phenotypes in Edis-depleted neurons. Furthermore, chromatin immunoprecipitation analysis reveals that the immune transcription factor Relish occupies two sites at the castor promoter, and that both sites are required for optimal castor gene activation induced by either immune challenge or Edis depletion. Lastly, Relish mutation rescues both the castor hyperactivation phenotype and neuronal defects in Edis knockdown animals. We conclude that the circular RNA Edis acts through Relish and castor to regulate neuronal development.

2022-10-04 | GSE196213 | GEO

Sensing self and nonself circular RNAs

Project description:Circular RNAs (circRNAs) are single-stranded RNAs that are joined head to tail. Initially discovered as pathogen genomes such as hepatitis D virus (HDV) and plant viroids, circRNAs are recently recognized as a pervasive class of noncoding RNAs in eukaryotic cells, generated through back splicing. circRNAs have been postulated to function in cell-to-cell information transfer or memory due to their extraordinary stability. Whether and how circRNAs trigger immune recognition is not known. Here we show that exogenous circular RNAs potently stimulate immune signaling, and mammalian cells sense self vs. nonself circRNAs via circRNA biogenesis. Transfection of purified in vitro spliced circRNA into mammalian cells led to potent induction of innate immunity genes. The nucleic acid sensor RIG-I is necessary and sufficient to sense foreign circRNA, and RIG-I and foreign circRNA co-aggregate in cytoplasmic foci. CircRNA activation of innate immunity is independent of 5’ triphosphate, double-stranded RNA structure, or primary sequence of the foreign circRNA. Instead, self-nonself discrimination depends on the intron that programs the circRNA. Use of a human intron to express a foreign circRNA sequence abrogates immune activation, and the mature human circRNA is associated with diverse RNA binding proteins reflecting its endogenous splicing and biogenesis. These results reveal innate immune sensing of circRNA, a prevalent class of host and pathogen RNAs, and highlight introns—the predominant output of mammalian transcription—as unexpected arbiters of self-nonself identity in the RNA world.

2017-06-29 | GSE81345 | GEO

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2015-04-24 | E-GEOD-65926 | biostudies-arrayexpress

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Structured elements drive circular RNA translation and expand the human proteome, part3

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2021-08-25 | PXD025233 | Pride

Structured elements drive circular RNA translation and expand the human proteome part2

Project description:The human genome encodes tens of thousands circular RNAs (circRNAs) whose levels correlate with many disease states. While studies have focused on the non-coding functions of circRNAs, emerging evidence suggests that a handful of circRNAs encode proteins. Translation canonically starts by recognition of mRNA 5’cap and scanning to the start codon; how circRNA translation initiates remains unclear. Here, we developed a high-throughput screen to systematically identify and quantify RNA sequences that can direct circRNA translation. We identify and validate over 17,000 circRNA internal ribosome entry sites (IRES) and reveal that 18S rRNA complementarity and a structured RNA element on the IRES are important for facilitating circRNA cap-independent translation. With genomic and peptidomic analyses of the IRES, we identified nearly 1,000 putative endogenous protein-coding circRNAs and hundreds of translational units encoded by these circRNAs. We further characterized circFGFR1p, a protein encoded by circFGFR1, functions as a negative regulator of FGFR1 to suppress cell growth under stress conditions. The circRNA proteome may be important links among circRNA, biological control, and disease.

2021-08-23 | PXD025235 | Pride

Structured elements drive circular RNA translation and expand the human proteome, part1

Project description:The human genome encodes tens of thousands circular RNAs (circRNAs) whose levels correlate with many disease states. While studies have focused on the non-coding functions of circRNAs, emerging evidence suggests that a handful of circRNAs encode proteins. Translation canonically starts by recognition of mRNA 5’cap and scanning to the start codon; how circRNA translation initiates remains unclear. Here, we developed a high-throughput screen to systematically identify and quantify RNA sequences that can direct circRNA translation. We identify and validate over 17,000 circRNA internal ribosome entry sites (IRES) and reveal that 18S rRNA complementarity and a structured RNA element on the IRES are important for facilitating circRNA cap-independent translation. With genomic and peptidomic analyses of the IRES, we identified nearly 1,000 putative endogenous protein-coding circRNAs and hundreds of translational units encoded by these circRNAs. We further characterized circFGFR1p, a protein encoded by circFGFR1, functions as a negative regulator of FGFR1 to suppress cell growth under stress conditions. The circRNA proteome may be important links among circRNA, biological control, and disease.

2021-08-23 | PXD024993 | Pride

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