ArticlePLoS genetics2017
Conserved properties of Drosophila Insomniac link sleep regulation and synaptic function.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 41 citations in OpenAlex.
- A Global Analysis of the Complex Structural Organization of KCTD Proteins and Their Functional Implications.International journal of molecular sciences · 2026Review
- Restoring brain wiring, mobility, sleep, and lifespan with a novel repurposed modulator of voltage-gated KJournal of translational medicine · 2026Article
- 25 years ofFly · 2025Review
- Targeted single cell expression profiling identifies integrators of sleep and metabolic state.G3 (Bethesda, Md.) · 2025Article
- Enhanced memory despite severe sleep loss in Drosophila insomniac mutants.PLoS biology · 2025Article
- The Cul3 ubiquitin ligase engages Insomniac as an adaptor to impact sleep and synaptic homeostasis.PLoS genetics · 2025Article
- Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Neuronal knockdown of Cullin3 as a Drosophila model of autism spectrum disorder.Scientific reports · 2024Article
- Article
- KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family.International journal of molecular sciences · 2023Article
- Structural basis for the ubiquitination of G protein βγ subunits by KCTD5/Cullin3 E3 ligase.Science advances · 2023Article
- Excessive daytime sleepiness: an emerging marker of cardiovascular risk.Heart (British Cardiac Society) · 2022Review
- Ubiquitin proteasome system in circadian rhythm and sleep homeostasis: Lessons from Drosophila.Genes to cells : devoted to molecular & cellular mechanisms · 2022Review
- Synaptic dysfunction connects autism spectrum disorder and sleep disturbances: A perspective from studies in model organisms.Sleep medicine reviews · 2022Review
- Article
- Emerging and converging molecular mechanisms in dystonia.Journal of neural transmission (Vienna, Austria : 1996) · 2021Review
- Genetic Dystonias: Update on Classification and New Genetic Discoveries.Current neurology and neuroscience reports · 2021Review
- Neurogenetic basis for circadian regulation of metabolism by the hypothalamus.Genes & development · 2019Review
- Article
- The Structural Versatility of the BTB Domains of KCTD Proteins and Their Recognition of the GABABiomolecules · 2019Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Sleep is an ancient animal behavior that is regulated similarly in species ranging from flies to humans. Various genes that regulate sleep have been identified in invertebrates, but whether the functions of these genes are conserved in mammals remains poorly explored. Drosophila insomniac (inc) mutants exhibit severely shortened and fragmented sleep. Inc protein physically associates with the Cullin-3 (Cul3) ubiquitin ligase, and neuronal depletion of Inc or Cul3 strongly curtails sleep, suggesting that Inc is a Cul3 adaptor that directs the ubiquitination of neuronal substrates that impact sleep. Three proteins similar to Inc exist in vertebrates-KCTD2, KCTD5, and KCTD17-but are uncharacterized within the nervous system and their functional conservation with Inc has not been addressed. Here we show that Inc and its mouse orthologs exhibit striking biochemical and functional interchangeability within Cul3 complexes. Remarkably, KCTD2 and KCTD5 restore sleep to inc mutants, indicating that they can substitute for Inc in vivo and engage its neuronal targets relevant to sleep. Inc and its orthologs localize similarly within fly and mammalian neurons and can traffic to synapses, suggesting that their substrates may include synaptic proteins. Consistent with such a mechanism, inc mutants exhibit defects in synaptic structure and physiology, indicating that Inc is essential for both sleep and synaptic function. Our findings reveal that molecular functions of Inc are conserved through ~600 million years of evolution and support the hypothesis that Inc and its orthologs participate in an evolutionarily conserved ubiquitination pathway that links synaptic function and sleep regulation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.