Degradation of the Neurospora circadian clock protein FREQUENCY through the ubiquitin-proteasome pathway.
Phosphorylation of the Neurospora circadian clock protein FREQUENCY (FRQ) promotes its degradation through the ubiquitin-proteasome pathway. Ubiquitination of FRQ requires FWD-1 (F-box/WD-40 repeat-containing protein-1), which is the substrate-recruiting subunit of an SCF (SKP/Cullin/F-box)-type ubiquitin ligase. In the fwd-1 mutant strains, FRQ degradation is defective, resulting in the accumulation of hyperphosphorylated FRQ and the loss of the circadian rhythmicities. The CSN (COP9 signalosome) promotes the function of SCF complexes in vivo. But in vitro, deneddylation of cullins by CSN inhibits SCF activity. In Neurospora, the disruption of the csn-2 subunit impairs FRQ degradation and compromises the normal circadian functions. These defects are due to the dramatically reduced levels of FWD-1 in the csn-2 mutant, a result of its rapid degradation. Other components of the SCF(FWD-1) complex, SKP-1 and CUL-1 are also unstable in the mutant. These results establish important roles for SCF(FWD-1) and CSN in the circadian clock of Neurospora and suggest that they are conserved components of the eukaryotic circadian clocks. In addition, these findings resolve the CSN paradox and suggest that the major function of CSN is to maintain the stability of SCF ubiquitin ligases in vivo.
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Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Liu
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D001683:Biological Clocks / Q000502:physiology*; D056926:CLOCK Proteins; D000075686:COP9 Signalosome Complex; D002940:Circadian Rhythm; D046912:Multiprotein Complexes / Q000378:metabolism; D009492:Neurospora crassa / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D046912:Multiprotein Complexes; D015534:Trans-Activators; D025801:Ubiquitin; D056926:CLOCK Proteins; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex