title: The COP9 signalosome is required for light-dependent timeless degradation and Drosophila clock resetting.
abstract: The ubiquitin-proteasome system plays a major role in the rhythmic accumulation and turnover of molecular clock components. In turn, these approximately 24 h molecular rhythms drive circadian rhythms of behavior and physiology. In Drosophila, the ubiquitin-proteasome system also plays a critical role in light-dependent degradation of the clock protein Timeless (TIM), a key step in the entrainment of the molecular clocks to light-dark cycles. Here, we investigated the role of the COP9 signalosome (CSN), a general regulator of protein degradation, in fly circadian rhythms. We found that null mutations in the genes encoding the CSN4 and CSN5 subunits prevent normal TIM degradation by light in the pacemaker lateral neurons (LNs) as does LN-specific expression of a dominant-negative CSN5 transgene. These defects are accompanied by strong reductions in behavioral phase shifts of adult flies lacking normal CSN5 activity in LNs. Defects in TIM degradation and resetting of behavioral phases were rescued by overexpression of Jetlag (JET), the F-box protein required for light-mediated TIM degradation. Flies lacking normal CSN activity in all clock neurons are rhythmic in constant light, a phenotype previously associated with jet mutants. Together, these data indicate that JET and the CSN lie in a common pathway leading to light-dependent TIM degradation. Surprisingly, we found that manipulations that strongly inhibit CSN activity had minimal effects on circadian rhythms in constant darkness, indicating a specific role for the CSN in light-mediated TIM degradation.
authors.affiliation: Department of Biology, New York University, New York, New York 10003, USA.
authors.forename: Alyson
authors.initials: A
authors.lastname: Knowles
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Koh
authors.forename: June-Tai
authors.initials: JT
authors.lastname: Wu
authors.forename: Cheng-Ting
authors.initials: CT
authors.lastname: Chien
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Chamovitz
authors.forename: Justin
authors.initials: J
authors.lastname: Blau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000166:cytology; D000075686:COP9 Signalosome Complex; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D007814:Larva; D008027:Light; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000145:classification / Q000235:genetics / Q000502:physiology*; D009991:Oscillometry; D010447:Peptide Hydrolases / Q000235:genetics / Q000502:physiology; D017956:Photoreceptor Cells, Invertebrate; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C520406:CSN4 protein, Drosophila; D029721:Drosophila Proteins; D044783:F-Box Proteins; C511696:JET protein, Drosophila; D009687:Nuclear Proteins; C096445:tim protein, Drosophila; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex