Proteogenomics of Adenosine-to-Inosine RNA Editing in the Fruit Fly

Kuznetsova, Ksenia G.; Kliuchnikova, Anna A.; Ilina, Irina U.; Chernobrovkin, Alexey; Novikova, Svetlana; Farafonova, T. E.; Карпов, Д. С.; Ivanov, Mark V.; Goncharov, Anton O.; Ilgisonis, Ekaterina V.; Voronko, O. E.; Nasaev, Shamsudin S.; Zgoda, Victor G.; Zubarev, Roman A.; Gorshkov, Mikhail V.; Moshkovskii, Sergei A.

doi:10.1021/acs.jproteome.8b00553

Cited by 18 publications

(68 citation statements)

References 76 publications

(217 reference statements)

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“…Two ion channels should be mentioned, the metabotropic glutamate receptor 4 (GRM4) and the voltage‐dependent T‐type calcium channel subunit alpha‐1G (CACNA1G). Notably, the latter is functionally related to a fruit fly protein, CG4587, which was shown to be extensively edited in previous work . Unexpectedly, among the edited proteins of murine brain, two enzymes with mitochondrial localization were found, specifically, ACOT10 and ME3.…”

Section: Resultsmentioning

confidence: 72%

“…The calcium‐dependent secretion activator 1 (CADPS) is shown to participate in calcium‐dependent release of synaptic vesicles . This was the only protein from our list whose ortholog was also edited in the fruit fly proteome . The set of edited proteins in mammals and fruit fly is substantially different, with components of presynaptic release mechanisms mostly edited in the insect.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, the parameters of label‐free quantitation between genomic and edited are supposed to be incomparable. The problem may be solved using targeted mass‐spectrometric methods with isotopically labeled peptide standards, as shown before for RNA editing in the fruit fly . In this work, which based on analysis of shotgun proteomic big data, the only measure of editing abundance remains spectral counting for edited peptides as listed in Tables and .…”

Section: Resultsmentioning

confidence: 99%

“…A pioneering work has described the RNA editome and the proteome of a cephalopod species called Californian octopus, which uses editing of RNA and further modifying the sequences of the corresponding proteins for adopting its poikilothermic body to environmental changes . Also, RNA editing at the proteome level was characterized for the fruit fly brain, in which about 70 edited sites were identified . Quantitative analysis of selected sites using targeted MS has shown that some of brain proteins were edited in up to 70% of adult insects.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine‐to‐Inosine RNA Editing in Mouse and Human Brain Proteomes

et al. 2019

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Proteogenomics is based on the use of customized genome or RNA sequencing databases for interrogation of shotgun proteomics data in search for proteome‐level evidence of genome variations or RNA editing. In this work, the products of adenosine‐to‐inosine RNA editing in human and murine brain proteomes are identified using publicly available brain proteome LC‐MS/MS datasets and an RNA editome database compiled from several sources. After filtering of false‐positive results, 20 and 37 sites of editing in proteins belonging to 14 and 32 genes are identified for murine and human brain proteomes, respectively. Eight sites of editing identified with high spectral counts overlapped between human and mouse brain samples. Some of these sites have been previously reported using orthogonal methods, such as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptors, CYFIP2, coatomer alpha. Also, differential editing between neurons and microglia is demonstrated in this work for some of the proteins from primary murine brain cell cultures. Because many edited sites are still not characterized functionally at the protein level, the results provide a necessary background for their further analysis in normal and diseased cells and tissues using targeted proteomic approaches.

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adenosine‐to‐Inosine RNA Editing in Mouse and Human Brain Proteomes

et al. 2019

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“…Coding RNA editing events in mRNA were mostly studied in transcripts [22], and only a few works used mass-spectrometry data to identify amino acid substitutions generated by transcriptome-wide ADAR activity. This was studied for human cancers [21], murine and human brains [17], as well as fruit fly's body, head and brain [16].…”

Section: Introductionmentioning

confidence: 99%

Proteome-Wide Analysis of ADAR-mediated Messenger RNA Editing During Fruit Fly Ontogeny

Kliuchnikova

Goncharov

Levitsky

et al. 2020

Preprint

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Moshkovskii S.A.). Highlights• Proteogenomic approach was applied to shotgun proteomics data of fruit fly ontogeny for identification of proteoforms originating from adenosine-to-inosine RNA editing.• Edited proteins identified at all life cycle stages are enriched in annotated protein-protein interactions at statistically significant level with many of them associated with actomyosin and synaptic vesicle functions.• Proteome-wide RNA editing event profiles were found specific to life cycle phase and independent of the protein abundances.• A majority of RNA editing events at the protein level was observed after metamorphosis in late pupae to adult insects, which was consistent with transcriptome data.• Targeted proteomic analysis of five selected edited sites and their genomic counterparts in brains for three phases of the fruit fly life cycle have demonstrated a clear increase in editing rate of up to 80% for the endophilin A protein in adult flies. AbstractAdenosine-to-inosine RNA editing is an enzymatic post-transcriptional modification which modulates immunity and neural transmission in multicellular organisms. Some of its functions are enforced through editing of mRNA codons with the resulting amino acid substitutions. We identified these sites originated from the RNA editing for developmental proteomes of Drosophila melanogaster at the protein level using available proteomic data for fifteen stages of fruit fly development from egg to imago and fourteen time points of embryogenesis. In total, 42 sites each belonging to a unique protein were found including four sites related to embryogenesis. The interactome analysis has revealed that most of the edited proteins are associated with synaptic vesicle trafficking and actomyosin organization. Quantitation data analysis suggested the existence of phase-specific RNA editing regulation by yet unknown mechanisms. These results support transcriptome analyses showing that a burst in RNA editing occurs during insect metamorphosis from pupa to imago. Further, targeted proteomics was employed to quantify edited and genomically encoded versions of five proteins in brains of larvae, pupae, and imago insects showing a clear trend towards an increase in editing rate for all of them. Our results may help to reveal the protein functions in physiological effects of RNA editing. SignificanceAdenosine-to-inosine RNA editing has multiple effects on body functions in many multicellular organisms from insects and molluscs to humans. Recent studies show that at least some of these effects are mediated by changes in protein sequences due to editing of codons in mRNA. However, it is not known how exactly the edited proteins can participate in RNA editing-mediated pathways.Moreover, most studies of edited proteins are based on the deduction of protein sequence changes from analysis of transcriptome without measurements of proteins themselves. Earlier, we explored for the first time the edited proteins of Drosophila melanogaster proteome. In this work, we continued the proteome-wide ana...

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