A role for the proteasome in the light response of the timeless clock protein.
The cyclic expression of the period (PER) and timeless (TIM) proteins is critical for the molecular circadian feedback loop in Drosophila. The entrainment by light of the circadian clock is mediated by a reduction in TIM levels. To elucidate the mechanism of this process, the sensitivity of TIM regulation by light was tested in an in vitro assay with inhibitors of candidate proteolytic pathways. The data suggested that TIM is degraded through a ubiquitin-proteasome mechanism. In addition, in cultures from third-instar larvae, TIM degradation was blocked specifically by inhibitors of proteasome activity. Degradation appeared to be preceded by tyrosine phosphorylation. Finally, TIM was ubiquitinated in response to light in cultured cells.
Naidoo
N
N
Howard Hughes Medical Institute, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Song
W
W
Hunter-Ensor
M
M
Sehgal
A
A
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001683:Biological Clocks; D002478:Cells, Cultured; D002940:Circadian Rhythm; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003624:Darkness; D004330:Drosophila; D029721:Drosophila Proteins; D005246:Feedback; D019476:Insect Proteins / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008027:Light; D009097:Multienzyme Complexes / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D014452:Ubiquitins / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D029721:Drosophila Proteins; D019476:Insect Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D014452:Ubiquitins; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C096445:tim protein, Drosophila; C067713:lactacystin; D019000:Phosphotyrosine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D007930:Leucine; C012211:ubenimex; C032854:leupeptin; D000111:Acetylcysteine