title: FWD1-mediated degradation of FREQUENCY in Neurospora establishes a conserved mechanism for circadian clock regulation.
abstract: Phosphorylation of the Neurospora circadian clock protein FREQUENCY (FRQ) regulates its degradation and the proper function of the clock. The mechanism by which FRQ undergoes degradation has not been established. Here we show that FRQ is likely ubiquitylated in vivo, and its proper degradation requires FWD1, an F-box/WD-40 repeat-containing protein. In the fwd1 disruption strains, FRQ degradation is severely impaired, resulting in the accumulation of hyperphosphorylated FRQ. Furthermore, the circadian rhythms of gene expression and the circadian conidiation rhythms are abolished in these fwd1 mutants. Finally, FRQ and FWD1 interact physically in vivo, suggesting that FWD1 is the substrate-recruiting subunit of an SCF-type ubiquitin ligase responsible for FRQ ubiquitylation and degradation. Together with the recent finding that Slimb (the Drosophila homolog of FWD1) is involved in the degradation of the Period protein in flies, our results indicate that FWD1 regulates the degradation of FRQ in Neurospora and is an evolutionarily conserved component of the eukaryotic circadian clock.
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: He
authors.forename: Ping
authors.initials: P
authors.lastname: Cheng
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Yang
authors.forename: Qiyang
authors.initials: Q
authors.lastname: He
authors.forename: Hongtao
authors.initials: H
authors.lastname: Yu
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005800:Genes, Fungal; D046911:Macromolecular Substances; D008954:Models, Biological; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009491:Neurospora / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D054830:Sesterterpenes; D013729:Terpenes / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C087405:FRQ protein, Neurospora crassa; D005656:Fungal Proteins; D046911:Macromolecular Substances; D054830:Sesterterpenes; D013729:Terpenes; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; C110233:slmb protein, Drosophila; C040764:ophiobolin A; D044767:Ubiquitin-Protein Ligases; D019204:GTP-Binding Proteins