The E3 ubiquitin ligase adaptor Tango10 links the core circadian clock to neuropeptide and behavioral rhythms

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 47; pp. 1 - 12
• Main Authors: Lee, Jongbin, Lim, Chunghun, Han, Tae Hee, Andreani, Tomas, Moye, Matthew, Curran, Jack, Johnson, Eric, Kath, William L., Diekman, Casey O., Lear, Bridget C., Allada, Ravi
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.11.2021
• Subjects: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Biological clocks; Biological Sciences; Circadian Clocks - physiology; Circadian rhythms; Clock gene; Cullin; Cullin Proteins - genetics; Cullin Proteins - metabolism; Depletion; Drosophila; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Electrophysiology; Genetic screening; Golgi apparatus; Mass spectrometry; Mass spectroscopy; Molecular oscillations; Mutants; Nerve endings; Neurons; Neurons - metabolism; Neuropeptides; Neuropeptides - genetics; Neuropeptides - metabolism; Oscillators; Pacemakers; Pigment-dispersing factor; Potassium; Potassium channels (voltage-gated); Potassium currents; Proteomics; Sleep; Sleep and wakefulness; Transcription; Transport buildings, stations and terminals; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; neuronal output; ubiquitin ligase; circadian rhythms; Drosophila; potassium current
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2110767118

Circadian transcriptional timekeepers in pacemaker neurons drive profound daily rhythms in sleep and wake. Here we reveal a molecular pathway that links core transcriptional oscillators to neuronal and behavioral rhythms. Using two independent genetic screens, we identified mutants of Transport and Golgi organization 10 (Tango10) with poor behavioral rhythmicity. Tango10 expression in pacemaker neurons expressing the neuropeptide PIGMENT-DISPERSING FACTOR (PDF) is required for robust rhythms. Loss of Tango10 results in elevated PDF accumulation in nerve terminals even in mutants lacking a functional core clock. TANGO10 protein itself is rhythmically expressed in PDF terminals. Mass spectrometry of TANGO10 complexes reveals interactions with the E3 ubiquitin ligase CULLIN 3 (CUL3). CUL3 depletion phenocopies Tango10 mutant effects on PDF even in the absence of the core clock gene timeless. Patch clamp electrophysiology in Tango10 mutant neurons demonstrates elevated spontaneous firing potentially due to reduced voltage-gated Shaker-like potassium currents. We propose that Tango10/Cul3 transduces molecular oscillations from the core clock to neuropeptide release important for behavioral rhythms.